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Galectin-3 – A jack-of-all-trades in cancer
Cancer Letters 313 (2011) 123–128
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Cancer Letters journal homepage: www.elsevier.com/locate/canlet
Mini-review
Galectin-3 – A jack-of-all-trades in cancer Anna U. Newlaczyl a, Lu-Gang Yu b,⇑ a b
Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK Department of Gastroenterology, Institute of Translational Medicine, The Henry Wellcome Lab, University of Liverpool, Liverpool L69 3GE, UK
a r t i c l e
i n f o
Article history: Received 20 July 2011 Received in revised form 1 September 2011 Accepted 2 September 2011
Keywords: Galectin-3 Cancer adhesion Progression Metastasis
a b s t r a c t Galectin-3 is a mammalian b-galactoside-binding protein that is expressed by various types of human cells. Changes in galectin-3 expression and subcellular and intercellular localizations are commonly seen in cancer and pre-cancerous conditions. It is increasingly recognized that galectin-3 is an important regulator of a broad range of cancer cell activities and plays important roles in cancer cell growth, transformation, apoptosis, angiogenesis, adhesion, invasion and metastasis. Such a divergent influence of galectin-3 on cancer cell activities derives from its multiple inter- and sub-cellular localizations where it interacts with a range of different binding partners. This mini-review summaries the diverse influences of galectin-3 on cancer cell behaviours with particular emphasis on its role in tumorigenesis and metastasis. Ó 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Galectins are a family of mammalian b-galactosidebinding proteins that share highly conserved carbohydrate recognition domains (CRDs) [1]. To date, 15 galectin members have been identified and they are classified into three subgroups depending on their structural differences and the number of CRDs within their polypeptide chains [2]. The prototypical galectins (galectin-1, -2, -5, -7, -10, -11, -13, -14 and -15) contain one CRD whereas the tandemrepeat galectins (galectin-4, -6, -8, -9 and -12) have two CRDs that are separated by a linker region in a single polypetide chain. Galectin-3 is the exclusive member of the chimera-type galectin subgroup and contains one CRD that is connected to an extended non-lectin N-terminal domain (Fig 1). Galectin-3 is one of the most studied galectins in the galectin family. It was first characterised as a 32 kDa antigen (Mac-2) on the surface of murine macrophages [3]. It is also known as CBP-35, HL-29, RL-29, IgEBP, hL-31 and LBP, due to its isolation from different species and also from dif-
⇑ Corresponding author. Tel.: +44 151 7946820; fax: +44 151 7946825. E-mail address: [email protected] (L.-G. Yu). 0304-3835/$ - see front matter Ó 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.canlet.2011.09.003
ferent laboratories [4]. Changes in galectin-3 expression are commonly seen in cancer and pre-cancerous conditions [2]. Increasing evidence shows that galectin-3 is involved in the regulation of diverse cancer cell activities that contribute to tumourigenesis, cancer progression and metastasis. 1.1. Galectin-3 structure Galectin-3 comprises of one CRD at its C-terminus and an unusual flexible 110–130 amino acids, N-terminal domain (ND) [4,5]. The galectin-3 ND consists of 7–14 repeats of a 9-amino acid sequence: Pro-Gly-Ala-Tyr-Pro-Gly-X-XX, and is sometimes referred to as a collagen-like ND due to its homology to collagen a1 (II) chain [6]. The structure of galectin-3 remains highly conserved across animal kingdom and is also unique in the galectin family [7]. The ND of galectin-3 is essential for galectin-3 multimerization and is sensitive to proteolysis by MMP-2 and MMP-9 matrix metalloproteinases [8,9]. The first 12 amino acids of the galectin-3 ND are necessary for galectin-3 secretion as well as for galectin-3 nuclear translocation [10,11] whilst the highly conserved Ser6 residue is involved in the anti-apoptotic activity of galectin-3 [12]. It has been reported that the Tyr102 residue at the ND may
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Galectin-3 dimerization C-terminal CRD domain PGAYPG(x)1-4 repeat domain
ligands
N-terminal domain Galectin-3 monomer
Galectin-3 polymerization with its carbohydrate ligands
Fig. 1. Schematic representations of the monomeric structure of galectin-3 and galectin-3 dimerization through its C-terminus in the absence of binding ligand and polymerization through its N-terminus in the presence of carbohydrate binding ligands.
also participate in galectin-3 carbohydrate binding activity [13,14]. The C-terminal CRD of galectin-3 contains approximately 130 amino acids that form a globular structure with five- and six-stranded b-sheets arranged in a b-sandwich [13]. The CRD contains a NWGR (Asp-Trp-Gly-Arg) motif which is essential for galectin-3 binding to b-galactosides [15,16]. This NWGR motif is also present in the B-cell lymphoma 2 (Bcl2) family members of apoptosis regulators and is responsible for the anti-apoptotic activity of galectin-3 [17]. Galectin-3 binds more strongly to galactose-terminated glycans than to simple galactose. For example, lactose (Lac) and N-acetyllactosamine (LacNAc) are much stronger ligands for galectin-3 than galactose. LacNAc also shows to have a 5-times higher affinity for galectin-3 than Lac [13,18,19]. The galectin-3 ND has been shown to also contribute to the increased binding affinity of galectin-3 to larger oligosaccharides (extended Lac or LacNAc) as compared to other galectins [20]. This is due to a conformational change of galectin-3 after its initial interaction with its carbohydrate ligands [18]. Galectin-3 can also interact with many intracellular proteins by protein– protein interactions in a carbohydrate-independent manner [21–25]. 1.2. Galectin-3 localisation and multimerisation Galectin-3, synthesized in the cell cytoplasm, shuttles between the cytoplasm and nucleus. It can also be secreted to the cell surface and biological fluids [4] through a nonclassical extocytosis process [11,26]. Galectin-3 translocation from cytoplasm to the nucleus is attributed to its ND [10] although some evidence also suggests the involvement of its CRD [27]. The movement of galectin-3 from nucleus to the cytoplasm, on the other hand, involves a nuclear export
sequence located within its CRD [28]. In the cytoplasm, galectin-3 can bind to Bcl-2 and inhibit cell apoptosis [17]. Cytoplasmic galectin-3 can also interact with the activated GTP-bound K-Ras [21,29] and affect Ras-mediated Akt signaling [30,31]. In the nucleus, galectin-3 promotes pre-mRNA splicing and participates in spliceosome assembly via complexes with nuclear protein Gemin4 [2,4]. Nuclear galectin-3 can also regulate gene transcription by enhancing transcription factor association with Spi1 and CRE elements in the gene promoter sequences [4]. In solution, galectin-3 largely occurs as a monomer [32]. It can also form homodimer by self-association through its CRDs in the absence of its binding ligands [33]. However, in the presence of its carbohydrate binding ligands, galectin-3 can polymerize up to pentamers through its ND (Fig. 1) [8,33,34]. Multimerisation is a common feature of extracellular galectin-3, where it often cross-links its cell surface ligands to form lattice-like structures [34,35] and triggers the initiation of cell surface molecule-associated cell signaling [2,36,37]. Galectin-3 is widely expressed in human tissues, including immune cells, epithelial cells and sensory neurons [4,38]. During early stages of human embryogenesis, however, galectin-3 shows a more specific expression pattern, mainly in the epithelia, kidney, chondrocytes and the liver [4]. Interestingly, galectin-3 knock-out mice remain viable and display no obvious abnormalities [16], indicating possible redundant or replaceable role of galectin-3 by other galectin members in normal physiological conditions. Conversely, galectin-3 overexpression is a predominant feature of many cancers. There is also a general shift of galectin-3 localization from nucleus to the cytoplasm in cancer development from adenoma to carcinoma [39,40]. There is strong evidence showing the involvements of altered galectin-3 expression and localization in the regulation of a broad range of cancer cell activates,
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such as cancer cell growth, transformation, apoptosis, immunosuppression, angiogenesis, adhesion, invasion and metastasis (Fig 2). 1.3. Galectin-3 in tumour transformation Substantial evidence indicates that galectin-3 overexpression promotes neoplastic transformation [21,36, 41,42]. In highly malignant human breast carcinoma cells, suppression of galectin-3 resulted in reversion of the altered cell morphology as well as in loss of anchorage- and serum-independent growth and led to the inhibition of tumour growth in immunologically suppressed mice [41]. Likewise, inhibition of galectin-3 expression by antisense cDNA in human thyroid papillary carcinoma cells led to suppression of anchorage-independent cell growth [42]. Furthermore, transfection of galectin-3 cDNA into normal thyroid follicular cells resulted in altered gene expression, loss of contact inhibition and serum-independent growth [43]. These results suggest that the maintenance of transformed phenotype of malignant breast and thyroid cells is closely associated with galectin-3 expression. The molecular mechanism of galectin-3-mediated transformation has shown to be partly attributed to the galectin-3 interaction with oncogenic K-Ras [21]. The galectin-3-Ras interaction enhances the Ras anchorage to the plasma member that causes constitutive activation of Ras-dependent phosphatidylinositol 3-kinase (PI3-K) and Raf-1 activation. The tumourigenic potential of galectin-3 may also involve the interactions of galectin-3 with b-catenin or various transcription factors that enhance the expressions of cyclin D and c-MYC [2,25] and promote cell cycle progression [4].
1.4. Galectin-3 in regulation of apoptosis Cytoplasmic galectin-3 is a well-known apoptotic inhibitor. Following apoptotic stimuli, cytoplasmic galectin-3 interacts with a calcium-dependent and phospholipidbinding protein synexin. This galectin-3-synexn interaction helps the translocation of galectin-3 to the mitochondria [44] where it interacts with Bcl-2 and blocks the alteration of mitochondrial membrane potential and cytochrome c release [44,45]. Nuclear galectin-3, on the other hand, has been shown to promote cell apoptosis in human prostate cancer cells [46,36]. The mechanism of this pro-apoptotic action of galectin-3 remains largely unknown but has been suggested to be linked with galectin-3 interaction with an apoptosis-associated protein Nucling [47]. Thus, galectin3 can be both anti- and pro-apoptotic dependent largely on its sub-cellular localizations.
1.5. Galectin-3 in immune regulation Extracellular galectin-3 can bind to the cell surface Nglycans and induce monocyte and T cell apoptosis during tumour cell evasion from the immune surveillance. Galectin-3 can suppress IL5 production and inhibit B lymphocyte differentiation. There is also evidence that galectin-3 can increase phagocytosis of neutrophils [48] and oxidative response of immune cells [49]. In human monocytes, galectin-3 is chemotactic and increases Ca2+ influx at high concentration (1 lM), whereas at low concentration (10–100 nM) it promotes chemokinesis [4,50]. Thus, galectin-3 regulates immune cell activities and contributes to immunosuppression in tumorigenesis and metastasis.
Circulating galectin-3 Disseminating tumour cell adhesion and survival promotion
Cytoplasmic galectin-3
Cell growth promotion
Apoptosis inhibition cell cycle promotion
Cancermatrix adhesion
Cell surface galectin-3
Transcription regulation
Galectin-3
Cancerendothelial adhesion Angiogenesis promotion Immune suppression
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mRNA splicing promotion Apoptosis promotion Nuclear galectin-3
Fig. 2. Divergent effects of galectin-3 on cancer cell activities at various intercellular and extracellular localizations.
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1.6. Galectin-3 in angiogenesis Formation of new blood vessels from pre-existing vessels – angiogenesis – is a crucial step in tumour cell invasion and metastasis [36]. Angiogenesis fuels tumours with essential oxygen and nutrients for excessive tumour growth. Exogenous galectin-3 has shown to enhance endothelial cell motility in vitro in cell culture and promotes new capillaries formation in vivo in mice [51]. This angiogenesis promoting effect of galectin-3 involves the interaction of galectin-3 with integrins or glycans expressed on cell surface molecules [52]. This causes clustering of galectin-3 with its cell surface ligands and the activation of focal adhesion kinase that leads to modulation of vascular endothelial growth factor (VEGF)- and basic fibroblast growth factor (bFGF)-mediated angiogenesis [53]. An interaction of galectin-3 with the endothelial cell surface enzyme aminopeptidase N/CD13 has also been reported to regulate endothelial vascularisation in the early steps of angiogenesis [54]. 1.7. Galectin-3 in cancer cell adhesion Tumour cell adhesion to and subsequent invasion through the extracellular matrix (ECM) at primary tumour sites are essential steps in epithelial cancer metastasis. Galectin-3 overexpression is associated with an increased invasiveness of many types of tumour cells such as neuroendocrine tumour pheochromocytoma, ovarian, melanoma, thyroid and colorectal cancer cells [4,55]. Overexpression of galectin-3 enhances tumour cell adhesion to ECM and promotes the escape of tumour cells from the primary tumour sites [37]. Such an effect of galectin-3 is attributed partly by its interaction with a range of the ECM glycoproteins such as fibronectins, collagen IV, elastin, and laminin [4]. The interaction of galectin-3 with cancer cell surface glycans such as the Mgat5-modified N-glycans [56], laminin and lysosome-associated membrane glycoproteins [4,55] has also shown to be involved in galectin-3-mediated cancer cell adhesion. The interaction of galectin-3 with cell surface epidermal growth factor receptor (EGFR) and transforming growth factor-b receptor (TGFbR) is believed to also contribute to the increased invasiveness of tumour cells. In this case, galectin-3 crosslinks these cell surface molecules and prevent their endocytosis and signalling. 1.8. Galectin-3 in tumour cell metastatic spreading Survival of the invaded tumour cells in the blood/lymphatic circulation and their subsequent adhesion to the blood vascular endothelium composes of important steps in cancer metastasis. Recent investigations have revealed that circulating galectin-3 may play a very important role in these processes [57]. Compared with that in healthy people, the level of circulating galectin-3 is significantly higher in the bloodstream of cancer patients in particular those with metastasis [58]. Higher level of circulating galectin-3 is associated with increased metastasis and poor prognosis in several types of cancers including colorectal, thyroid and ovarian cancer. It has been demonstrated recently that galectin-3 binds to the oncofoetal ThomsenFriedenreich (galactoseb1,3 N-acetylgalactosaminea, TF)
antigen on the transmembrane mucin MUC1 expressed on tumour cells [59]. The binding of galectin-3 to cancerassociated TF/MUC1 induces redistribution of MUC1 on the cell surface that allows the exposure of the smaller cell surface adhesion molecules which otherwise are concealed by the large and heavily glycosylated cell surface MUC1. This results in increased cancer cell heterotypic adhesion to the blood vascular endothelium [60] as well as increased cancer cell homotypic aggregation for the formation of tumour micro-emboli [61]. The formation of tumour microemboli enhances the survival of disseminating tumour cells in the circulation by preventing initiation of anoikis. Moreover, galectin-3 expressed on cancer as well as on endothelial cell surface can itself act as a cell adhesion molecule by interaction with the cancer- and endothelialassociated TF disaccharides and increase cancer cell heterotypic adhesion to vascular endothelium and cancer cell homotypic aggregation in cancer cell haematogenous dissemination in metastasis [62–64]. 2. Conclusion remarks As a multifunctional protein widely expressed by many types of human cells, galectin-3 overexpression and changes of sub- and inter-cellular localization are commonly seen in various types of human cancers. Although much remains to be further explored, more and more evidence indicates that galectin-3 is involved in the regulations of a myriad of cancer cell activities during cancer development, progression and metastasis. This is hugely attributed to the altered interactions of galectin-3 with a range of different binding partners at different locations in cancer conditions. Targeting the actions of galectin-3 will represent a promising therapeutic strategy for the development of effective therapeutic agents for cancer treatment. Acknowledgments The work in the authors’ laboratory was supported by Cancer Research UK Grant C7596 (to LGY) and North West Cancer Research Fund Grant CR777 (to LGY). References [1] S.H. Barondes, D.N. Cooper, M.A. Gitt, H. Leffler, Galectins. Structure and function of a large family of animal lectins, J. Biol. Chem. 269 (1994) 20807–20810. [2] R.Y. Yang, G.A. Rabinovich, F.T. Liu, Galectins: structure, function and therapeutic potential, Expert. Rev. Mol. Med. 10 (2008) e17. [3] M.K. Ho, T.A. Springer, Mac-2, a novel 32, 000 Mr mouse macrophage subpopulation-specific antigen defined by monoclonal antibodies, J. Immunol. 128 (1982) 1221–1228. [4] J. Dumic, S. Dabelic, M. Flogel, Galectin-3: an open-ended story, Biochim. Biophys. Acta 1760 (2006) 616–635. [5] B. Birdsall, J. Feeney, I.D. Burdett, S. Bawumia, E.A. Barboni, R.C. Hughes, NMR solution studies of hamster galectin-3 and electron microscopic visualization of surface-adsorbed complexes: evidence for interactions between the N- and C-terminal domains, Biochemistry 40 (2001) 4859–4866. [6] A. Raz, G. Pazerini, P. Carmi, Identification of the metastasisassociated, galactoside-binding lectin as a chimeric gene product with homology to an IgE-binding protein, Cancer Res. 49 (1989) 3489–3493.
A.U. Newlaczyl, L.-G. Yu / Cancer Letters 313 (2011) 123–128 [7] D. Houzelstein, I.R. Goncalves, A.J. Fadden, S.S. Sidhu, D.N. Cooper, K. Drickamer, H. Leffler, F. Poirier, Phylogenetic analysis of the vertebrate galectin family, Mol. Biol. Evol. 21 (2004) 1177–1187. [8] S.M. Massa, D.N. Cooper, H. Leffler, S.H. Barondes, L-29, an endogenous lectin, binds to glycoconjugate ligands with positive cooperativity, Biochemistry 32 (1993) 260–267. [9] J. Ochieng, B. Green, S. Evans, O. James, P. Warfield, Modulation of the biological functions of galectin-3 by matrix metalloproteinases, Biochim. Biophys. Acta 1379 (1998) 97–106. [10] H.C. Gong, Y. Honjo, P. Nangia-Makker, V. Hogan, N. Mazurak, R.S. Bresalier, A. Raz, The NH2 terminus of galectin-3 governs cellular compartmentalization and functions in cancer cells, Cancer Res. 59 (1999) 6239–6245. [11] R.P. Menon, R.C. Hughes, Determinants in the N-terminal domains of galectin-3 for secretion by a novel pathway circumventing the endoplasmic reticulum-Golgi complex, Eur. J. Biochem. 264 (1999) 569–576. [12] T. Yoshii, T. Fukumori, Y. Honjo, H. Inohara, H.R. Kim, A. Raz, Galectin-3 phosphorylation is required for its anti-apoptotic function and cell cycle arrest, J. Biol. Chem. 277 (2002) 6852–6857. [13] J. Seetharaman, A. Kanigsberg, R. Slaaby, H. Leffler, S.H. Barondes, J.M. Rini, X-ray crystal structure of the human galectin-3 carbohydrate recognition domain at 2.1-A resolution, J. Biol. Chem. 273 (1998) 13047–13052. [14] E.A. Barboni, S. Bawumia, K. Henrick, R.C. Hughes, Molecular modeling and mutagenesis studies of the N-terminal domains of galectin-3: evidence for participation with the C-terminal carbohydrate recognition domain in oligosaccharide binding, Glycobiology 10 (2000) 1201–1208. [15] S. Akahani, P. Nangia-Makker, H. Inohara, H.R. Kim, A. Raz, Galectin3: a novel antiapoptotic molecule with a functional BH1 (NWGR) domain of Bcl-2 family, Cancer Res. 57 (1997) 5272–5276. [16] C. Colnot, D. Fowlis, M.A. Ripoche, I. Bouchaert, F. Poirier, Embryonic implantation in galectin 1/galectin 3 double mutant mice, Dev. Dyn. 211 (1998) 306–313. [17] R.Y. Yang, D.K. Hsu, F.T. Liu, Expression of galectin-3 modulates T-cell growth and apoptosis, Proc. Natl. Acad. Sci. USA 93 (1996) 6737–6742. [18] N. Agrwal, Q. Sun, S.Y. Wang, J.L. Wang, Carbohydrate-binding protein 35. I: Properties of the recombinant polypeptide and the individuality of the domains, J. Biol. Chem. 268 (1993) 14932– 14939. [19] S. Sato, R.C. Hughes, Binding specificity of a baby hamster kidney lectin for H type I and II chains, polylactosamine glycans, and appropriately glycosylated forms of laminin and fibronectin, J. Biol. Chem. 267 (1992) 6983–6990. [20] J. Hirabayashi, T. Hashidate, Y. Arata, N. Nishi, T. Nakamura, M. Hirashima, T. Urashima, T. Oka, M. Futai, W.E. Muller, F. Yagi, K. Kasai, Oligosaccharide specificity of galectins: a search by frontal affinity chromatography, Biochim. Biophys. Acta 1572 (2002) 232–254. [21] G. Elad-Sfadia, R. Haklai, E. Balan, Y. Kloog, Galectin-3 augments KRas activation and triggers a Ras signal that attenuates ERK but not phosphoinositide 3-kinase activity, J. Biol. Chem. 279 (2004) 34922– 34930. [22] R.P. Menon, M. Strom, R.C. Hughes, Interaction of a novel cysteine and histidine-rich cytoplasmic protein with galectin-3 in a carbohydrate-independent manner, FEBS Lett. 470 (2000) 227–231. [23] I. Paron, A. Scaloni, A. Pines, A. Bachi, F.T. Liu, C. Puppin, M. Pandolfi, L. Ledda, C. Di Loreto, G. Damante, G. Tell, Nuclear localization of Galectin-3 in transformed thyroid cells: a role in transcriptional regulation, Biochem. Biophys. Res. Commun. 302 (2003) 545–553. [24] T. Shimura, Y. Takenaka, T. Fukumori, S. Tsutsumi, K. Okada, V. Hogan, A. Kikuchi, H. Kuwano, A. Raz, Implication of galectin-3 in Wnt signaling, Cancer Res. 65 (2005) 3535–3537. [25] T. Shimura, Y. Takenaka, S. Tsutsumi, V. Hogan, A. Kikuchi, A. Raz, Galectin-3, a novel binding partner of beta-catenin, Cancer Res. 64 (2004) 6363–6367. [26] R.C. Hughes, Secretion of the galectin family of mammalian carbohydrate-binding proteins, Biochim. Biophys. Acta 1473 (1999) 172–185. [27] J.C. Gaudin, B. Mehul, R.C. Hughes, Nuclear localisation of wild type and mutant galectin-3 in transfected cells, Biol. Cell 92 (2000) 49–58. [28] Y.G. Tsay, N.Y. Lin, P.G. Voss, R.J. Patterson, J.L. Wang, Export of galectin-3 from nuclei of digitonin-permeabilized mouse 3T3 fibroblasts, Exp. Cell Res. 252 (1999) 250–261. [29] R. Shalom-Feuerstein, T. Cooks, A. Raz, Y. Kloog, Galectin-3 regulates a molecular switch from N-Ras to K-Ras usage in human breast carcinoma cells, Cancer Res. 65 (2005) 7292–7300.
127
[30] Y.J. Lee, Y.K. Song, J.J. Song, R.R. Siervo-Sassi, H.R. Kim, L. Li, D.R. Spitz, A. Lokshin, J.H. Kim, Reconstitution of galectin-3 alters glutathione content and potentiates TRAIL-induced cytotoxicity by dephosphorylation of Akt, Exp. Cell Res. 288 (2003) 21–34. [31] N. Oka, S. Nakahara, Y. Takenaka, T. Fukumori, V. Hogan, H.O. Kanayama, T. Yanagawa, A. Raz, Galectin-3 inhibits tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by activating Akt in human bladder carcinoma cells, Cancer Res. 65 (2005) 7546–7553. [32] S. Morris, N. Ahmad, S. Andre, H. Kaltner, H.J. Gabius, M. Brenowitz, F. Brewer, Quaternary solution structures of galectins-1, -3, and -7, Glycobiology 14 (2004) 293–300. [33] R.Y. Yang, P.N. Hill, D.K. Hsu, F.T. Liu, Role of the carboxyl-terminal lectin domain in self-association of galectin-3, Biochemistry 37 (1998) 4086–4092. [34] N. Ahmad, H.J. Gabius, S. Andre, H. Kaltner, S. Sabesan, R. Roy, B. Liu, F. Macaluso, C.F. Brewer, Galectin-3 precipitates as a pentamer with synthetic multivalent carbohydrates and forms heterogeneous cross-linked complexes, J. Biol. Chem. 279 (2004) 10841–10847. [35] C.F. Brewer, M.C. Miceli, L.G. Baum, Clusters, bundles, arrays and lattices: novel mechanisms for lectin-saccharide-mediated cellular interactions, Curr. Opin. Struct. Biol. 12 (2002) 616–623. [36] F.T. Liu, G.A. Rabinovich, Galectins as modulators of tumour progression, Nat. Rev. Cancer 5 (2005) 29–41. [37] J. Ochieng, V. Furtak, P. Lukyanov, Extracellular functions of galectin3, Glycoconj J. 19 (2004) 527–535. [38] R.C. Hughes, The galectin family of mammalian carbohydratebinding molecules, Biochem. Soc. Trans. 25 (1997) 1194–1198. [39] S. Andre, S. Kojima, N. Yamazaki, C. Fink, H. Kaltner, K. Kayser, H.J. Gabius, Galectins-1 and -3 and their ligands in tumor biology. Non-uniform properties in cell-surface presentation and modulation of adhesion to matrix glycoproteins for various tumor cell lines, in biodistribution of free and liposome-bound galectins and in their expression by breast and colorectal carcinomas with/ without metastatic propensity, J. Cancer Res. Clin. Oncol. 125 (1999) 461–474. [40] X. Sanjuan, P.L. Fernandez, A. Castells, V. Castronovo, F. van den Brule, F.T. Liu, A. Cardesa, E. Campo, Differential expression of galectin 3 and galectin 1 in colorectal cancer progression, Gastroenterology 113 (1997) 1906–1915. [41] Y. Honjo, P. Nangia-Makker, H. Inohara, A. Raz, Down-regulation of galectin-3 suppresses tumorigenicity of human breast carcinoma cells, Clin. Cancer Res. 7 (2001) 661–668. [42] T. Yoshii, H. Inohara, Y. Takenaka, Y. Honjo, S. Akahani, T. Nomura, A. Raz, T. Kubo, Galectin-3 maintains the transformed phenotype of thyroid papillary carcinoma cells, Int. J. Oncol. 18 (2001) 787– 792. [43] Y. Takenaka, H. Inohara, T. Yoshii, K. Oshima, S. Nakahara, S. Akahani, Y. Honjo, Y. Yamamoto, A. Raz, T. Kubo, Malignant transformation of thyroid follicular cells by galectin-3, Cancer Lett. 195 (2003) 111–119. [44] F. Yu, R.L. Finley Jr., A. Raz, H.R. Kim, Galectin-3 translocates to the perinuclear membranes and inhibits cytochrome c release from the mitochondria. A role for synexin in galectin-3 translocation, J. Biol. Chem. 277 (2002) 15819–15827. [45] P. Matarrese, N. Tinari, M.L. Semeraro, C. Natoli, S. Iacobelli, W. Malorni, Galectin-3 overexpression protects from cell damage and death by influencing mitochondrial homeostasis, FEBS Lett. 473 (2000) 311–315. [46] S. Califice, V. Castronovo, M. Bracke, F. van den Brule, Dual activities of galectin-3 in human prostate cancer: tumor suppression of nuclear galectin-3 vs tumor promotion of cytoplasmic galectin-3, Oncogene 23 (2004) 7527–7536. [47] L. Liu, T. Sakai, N. Sano, K. Fukui, Nucling mediates apoptosis by inhibiting expression of galectin-3 through interference with nuclear factor kappaB signalling, Biochem. J. 380 (2004) 31–41. [48] G.C. Fernandez, J.M. Ilarregui, C.J. Rubel, M.A. Toscano, S.A. Gomez, M. Beigier Bompadre, M.A. Isturiz, G.A. Rabinovich, M.S. Palermo, Galectin-3 and soluble fibrinogen act in concert to modulate neutrophil activation and survival: involvement of alternative MAPK pathways, Glycobiology 15 (2005) 519–527. [49] E. Feuk-Lagerstedt, E.T. Jordan, H. Leffler, C. Dahlgren, A. Karlsson, Identification of CD66a and CD66b as the major galectin-3 receptor candidates in human neutrophils, J. Immunol. 163 (1999) 5592– 5598. [50] H. Sano, D.K. Hsu, L. Yu, J.R. Apgar, I. Kuwabara, T. Yamanaka, M. Hirashima, F.T. Liu, Human galectin-3 is a novel chemoattractant for monocytes and macrophages, J. Immunol. 165 (2000) 2156– 2164.
128
A.U. Newlaczyl, L.-G. Yu / Cancer Letters 313 (2011) 123–128
[51] P. Nangia-Makker, Y. Honjo, R. Sarvis, S. Akahani, V. Hogan, K.J. Pienta, A. Raz, Galectin-3 induces endothelial cell morphogenesis and angiogenesis, Am. J. Pathol. 156 (2000) 899–909. [52] J. Fukushi, I.T. Makagiansar, W.B. Stallcup, NG2 proteoglycan promotes endothelial cell motility and angiogenesis via engagement of galectin-3 and alpha3beta1 integrin, Mol. Biol. Cell 15 (2004) 3580–3590. [53] A.I. Markowska, F.T. Liu, N. Panjwani, Galectin-3 is an important mediator of VEGF- and bFGF-mediated angiogenic response, J. Exp. Med. 207 (2010) 1981–1993. [54] E. Yang, J.S. Shim, H.J. Woo, K.W. Kim, H.J. Kwon, Aminopeptidase N/ CD13 induces angiogenesis through interaction with a proangiogenic protein, galectin-3, Biochem. Biophys. Res. Commun. 363 (2007) 336–341. [55] H. Barrow, J.M. Rhodes, L.-G. Yu, The role of galectins in colorectal cancer progression, Int. J. Cancer 129 (2011) 1–8. [56] A. Lagana, J.G. Goetz, P. Cheung, A. Raz, J.W. Dennis, I.R. Nabi, Galectin binding to Mgat5-modified N-glycans regulates fibronectin matrix remodeling in tumor cells, Mol. Cell Biol. 26 (2006) 3181–3193. [57] L.G. Yu, Circulating galectin-3 in the bloodstream: An emerging promoter of cancer metastasis, World J. Gastrointest Oncol. 2 (2010) 177–180. [58] I. Iurisci, N. Tinari, C. Natoli, D. Angelucci, E. Cianchetti, S. Iacobelli, Concentrations of galectin-3 in the sera of normal controls and cancer patients, Clin. Cancer Res. 6 (2000) 1389–1393.
[59] L.G. Yu, N. Andrews, Q. Zhao, D. McKean, J.F. Williams, L.J. Connor, O.V. Gerasimenko, J. Hilkens, J. Hirabayashi, K. Kasai, J.M. Rhodes, Galectin-3 interaction with Thomsen-Friedenreich disaccharide on cancer-associated MUC1 causes increased cancer cell endothelial adhesion, J. Biol. Chem. 282 (2007) 773–781. [60] Q. Zhao, X. Guo, G.B. Nash, P.C. Stone, J. Hilkens, J.M. Rhodes, L.G. Yu, Circulating galectin-3 promotes metastasis by modifying MUC1 localization on cancer cell surface, Cancer Res. 69 (2009) 6799–6806. [61] Q. Zhao, M. Barclay, J. Hilkens, X. Guo, H. Barrow, J.M. Rhodes, L.G. Yu, Interaction between circulating galectin-3 and cancer-associated MUC1 enhances tumour cell homotypic aggregation and prevents anoikis, Mol. Cancer 9 (2010) 154. [62] J. Zou, V.V. Glinsky, L.A. Landon, L. Matthews, S.L. Deutscher, Peptides specific to the galectin-3 carbohydrate recognition domain inhibit metastasis-associated cancer cell adhesion, Carcinogenesis 26 (2005) 309–318. [63] V.V. Glinsky, G.V. Glinsky, K. Rittenhouse-Olson, M.E. Huflejt, O.V. Glinskii, S.L. Deutscher, T.P. Quinn, The role of ThomsenFriedenreich antigen in adhesion of human breast and prostate cancer cells to the endothelium, Cancer Res. 61 (2001) 4851–4857. [64] S.K. Khaldoyanidi, V.V. Glinsky, L. Sikora, A.B. Glinskii, V.V. Mossine, T.P. Quinn, G.V. Glinsky, P. Sriramarao, MDA-MB-435 human breast carcinoma cell homo- and heterotypic adhesion under flow conditions is mediated in part by Thomsen-Friedenreich antigengalectin-3 interactions, J. Biol. Chem. 278 (2003) 4127–4134.
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Cancer Letters journal homepage: www.elsevier.com/locate/canlet
Mini-review
Galectin-3 – A jack-of-all-trades in cancer Anna U. Newlaczyl a, Lu-Gang Yu b,⇑ a b
Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK Department of Gastroenterology, Institute of Translational Medicine, The Henry Wellcome Lab, University of Liverpool, Liverpool L69 3GE, UK
a r t i c l e
i n f o
Article history: Received 20 July 2011 Received in revised form 1 September 2011 Accepted 2 September 2011
Keywords: Galectin-3 Cancer adhesion Progression Metastasis
a b s t r a c t Galectin-3 is a mammalian b-galactoside-binding protein that is expressed by various types of human cells. Changes in galectin-3 expression and subcellular and intercellular localizations are commonly seen in cancer and pre-cancerous conditions. It is increasingly recognized that galectin-3 is an important regulator of a broad range of cancer cell activities and plays important roles in cancer cell growth, transformation, apoptosis, angiogenesis, adhesion, invasion and metastasis. Such a divergent influence of galectin-3 on cancer cell activities derives from its multiple inter- and sub-cellular localizations where it interacts with a range of different binding partners. This mini-review summaries the diverse influences of galectin-3 on cancer cell behaviours with particular emphasis on its role in tumorigenesis and metastasis. Ó 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Galectins are a family of mammalian b-galactosidebinding proteins that share highly conserved carbohydrate recognition domains (CRDs) [1]. To date, 15 galectin members have been identified and they are classified into three subgroups depending on their structural differences and the number of CRDs within their polypeptide chains [2]. The prototypical galectins (galectin-1, -2, -5, -7, -10, -11, -13, -14 and -15) contain one CRD whereas the tandemrepeat galectins (galectin-4, -6, -8, -9 and -12) have two CRDs that are separated by a linker region in a single polypetide chain. Galectin-3 is the exclusive member of the chimera-type galectin subgroup and contains one CRD that is connected to an extended non-lectin N-terminal domain (Fig 1). Galectin-3 is one of the most studied galectins in the galectin family. It was first characterised as a 32 kDa antigen (Mac-2) on the surface of murine macrophages [3]. It is also known as CBP-35, HL-29, RL-29, IgEBP, hL-31 and LBP, due to its isolation from different species and also from dif-
⇑ Corresponding author. Tel.: +44 151 7946820; fax: +44 151 7946825. E-mail address: [email protected] (L.-G. Yu). 0304-3835/$ - see front matter Ó 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.canlet.2011.09.003
ferent laboratories [4]. Changes in galectin-3 expression are commonly seen in cancer and pre-cancerous conditions [2]. Increasing evidence shows that galectin-3 is involved in the regulation of diverse cancer cell activities that contribute to tumourigenesis, cancer progression and metastasis. 1.1. Galectin-3 structure Galectin-3 comprises of one CRD at its C-terminus and an unusual flexible 110–130 amino acids, N-terminal domain (ND) [4,5]. The galectin-3 ND consists of 7–14 repeats of a 9-amino acid sequence: Pro-Gly-Ala-Tyr-Pro-Gly-X-XX, and is sometimes referred to as a collagen-like ND due to its homology to collagen a1 (II) chain [6]. The structure of galectin-3 remains highly conserved across animal kingdom and is also unique in the galectin family [7]. The ND of galectin-3 is essential for galectin-3 multimerization and is sensitive to proteolysis by MMP-2 and MMP-9 matrix metalloproteinases [8,9]. The first 12 amino acids of the galectin-3 ND are necessary for galectin-3 secretion as well as for galectin-3 nuclear translocation [10,11] whilst the highly conserved Ser6 residue is involved in the anti-apoptotic activity of galectin-3 [12]. It has been reported that the Tyr102 residue at the ND may
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Galectin-3 dimerization C-terminal CRD domain PGAYPG(x)1-4 repeat domain
ligands
N-terminal domain Galectin-3 monomer
Galectin-3 polymerization with its carbohydrate ligands
Fig. 1. Schematic representations of the monomeric structure of galectin-3 and galectin-3 dimerization through its C-terminus in the absence of binding ligand and polymerization through its N-terminus in the presence of carbohydrate binding ligands.
also participate in galectin-3 carbohydrate binding activity [13,14]. The C-terminal CRD of galectin-3 contains approximately 130 amino acids that form a globular structure with five- and six-stranded b-sheets arranged in a b-sandwich [13]. The CRD contains a NWGR (Asp-Trp-Gly-Arg) motif which is essential for galectin-3 binding to b-galactosides [15,16]. This NWGR motif is also present in the B-cell lymphoma 2 (Bcl2) family members of apoptosis regulators and is responsible for the anti-apoptotic activity of galectin-3 [17]. Galectin-3 binds more strongly to galactose-terminated glycans than to simple galactose. For example, lactose (Lac) and N-acetyllactosamine (LacNAc) are much stronger ligands for galectin-3 than galactose. LacNAc also shows to have a 5-times higher affinity for galectin-3 than Lac [13,18,19]. The galectin-3 ND has been shown to also contribute to the increased binding affinity of galectin-3 to larger oligosaccharides (extended Lac or LacNAc) as compared to other galectins [20]. This is due to a conformational change of galectin-3 after its initial interaction with its carbohydrate ligands [18]. Galectin-3 can also interact with many intracellular proteins by protein– protein interactions in a carbohydrate-independent manner [21–25]. 1.2. Galectin-3 localisation and multimerisation Galectin-3, synthesized in the cell cytoplasm, shuttles between the cytoplasm and nucleus. It can also be secreted to the cell surface and biological fluids [4] through a nonclassical extocytosis process [11,26]. Galectin-3 translocation from cytoplasm to the nucleus is attributed to its ND [10] although some evidence also suggests the involvement of its CRD [27]. The movement of galectin-3 from nucleus to the cytoplasm, on the other hand, involves a nuclear export
sequence located within its CRD [28]. In the cytoplasm, galectin-3 can bind to Bcl-2 and inhibit cell apoptosis [17]. Cytoplasmic galectin-3 can also interact with the activated GTP-bound K-Ras [21,29] and affect Ras-mediated Akt signaling [30,31]. In the nucleus, galectin-3 promotes pre-mRNA splicing and participates in spliceosome assembly via complexes with nuclear protein Gemin4 [2,4]. Nuclear galectin-3 can also regulate gene transcription by enhancing transcription factor association with Spi1 and CRE elements in the gene promoter sequences [4]. In solution, galectin-3 largely occurs as a monomer [32]. It can also form homodimer by self-association through its CRDs in the absence of its binding ligands [33]. However, in the presence of its carbohydrate binding ligands, galectin-3 can polymerize up to pentamers through its ND (Fig. 1) [8,33,34]. Multimerisation is a common feature of extracellular galectin-3, where it often cross-links its cell surface ligands to form lattice-like structures [34,35] and triggers the initiation of cell surface molecule-associated cell signaling [2,36,37]. Galectin-3 is widely expressed in human tissues, including immune cells, epithelial cells and sensory neurons [4,38]. During early stages of human embryogenesis, however, galectin-3 shows a more specific expression pattern, mainly in the epithelia, kidney, chondrocytes and the liver [4]. Interestingly, galectin-3 knock-out mice remain viable and display no obvious abnormalities [16], indicating possible redundant or replaceable role of galectin-3 by other galectin members in normal physiological conditions. Conversely, galectin-3 overexpression is a predominant feature of many cancers. There is also a general shift of galectin-3 localization from nucleus to the cytoplasm in cancer development from adenoma to carcinoma [39,40]. There is strong evidence showing the involvements of altered galectin-3 expression and localization in the regulation of a broad range of cancer cell activates,
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such as cancer cell growth, transformation, apoptosis, immunosuppression, angiogenesis, adhesion, invasion and metastasis (Fig 2). 1.3. Galectin-3 in tumour transformation Substantial evidence indicates that galectin-3 overexpression promotes neoplastic transformation [21,36, 41,42]. In highly malignant human breast carcinoma cells, suppression of galectin-3 resulted in reversion of the altered cell morphology as well as in loss of anchorage- and serum-independent growth and led to the inhibition of tumour growth in immunologically suppressed mice [41]. Likewise, inhibition of galectin-3 expression by antisense cDNA in human thyroid papillary carcinoma cells led to suppression of anchorage-independent cell growth [42]. Furthermore, transfection of galectin-3 cDNA into normal thyroid follicular cells resulted in altered gene expression, loss of contact inhibition and serum-independent growth [43]. These results suggest that the maintenance of transformed phenotype of malignant breast and thyroid cells is closely associated with galectin-3 expression. The molecular mechanism of galectin-3-mediated transformation has shown to be partly attributed to the galectin-3 interaction with oncogenic K-Ras [21]. The galectin-3-Ras interaction enhances the Ras anchorage to the plasma member that causes constitutive activation of Ras-dependent phosphatidylinositol 3-kinase (PI3-K) and Raf-1 activation. The tumourigenic potential of galectin-3 may also involve the interactions of galectin-3 with b-catenin or various transcription factors that enhance the expressions of cyclin D and c-MYC [2,25] and promote cell cycle progression [4].
1.4. Galectin-3 in regulation of apoptosis Cytoplasmic galectin-3 is a well-known apoptotic inhibitor. Following apoptotic stimuli, cytoplasmic galectin-3 interacts with a calcium-dependent and phospholipidbinding protein synexin. This galectin-3-synexn interaction helps the translocation of galectin-3 to the mitochondria [44] where it interacts with Bcl-2 and blocks the alteration of mitochondrial membrane potential and cytochrome c release [44,45]. Nuclear galectin-3, on the other hand, has been shown to promote cell apoptosis in human prostate cancer cells [46,36]. The mechanism of this pro-apoptotic action of galectin-3 remains largely unknown but has been suggested to be linked with galectin-3 interaction with an apoptosis-associated protein Nucling [47]. Thus, galectin3 can be both anti- and pro-apoptotic dependent largely on its sub-cellular localizations.
1.5. Galectin-3 in immune regulation Extracellular galectin-3 can bind to the cell surface Nglycans and induce monocyte and T cell apoptosis during tumour cell evasion from the immune surveillance. Galectin-3 can suppress IL5 production and inhibit B lymphocyte differentiation. There is also evidence that galectin-3 can increase phagocytosis of neutrophils [48] and oxidative response of immune cells [49]. In human monocytes, galectin-3 is chemotactic and increases Ca2+ influx at high concentration (1 lM), whereas at low concentration (10–100 nM) it promotes chemokinesis [4,50]. Thus, galectin-3 regulates immune cell activities and contributes to immunosuppression in tumorigenesis and metastasis.
Circulating galectin-3 Disseminating tumour cell adhesion and survival promotion
Cytoplasmic galectin-3
Cell growth promotion
Apoptosis inhibition cell cycle promotion
Cancermatrix adhesion
Cell surface galectin-3
Transcription regulation
Galectin-3
Cancerendothelial adhesion Angiogenesis promotion Immune suppression
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mRNA splicing promotion Apoptosis promotion Nuclear galectin-3
Fig. 2. Divergent effects of galectin-3 on cancer cell activities at various intercellular and extracellular localizations.
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1.6. Galectin-3 in angiogenesis Formation of new blood vessels from pre-existing vessels – angiogenesis – is a crucial step in tumour cell invasion and metastasis [36]. Angiogenesis fuels tumours with essential oxygen and nutrients for excessive tumour growth. Exogenous galectin-3 has shown to enhance endothelial cell motility in vitro in cell culture and promotes new capillaries formation in vivo in mice [51]. This angiogenesis promoting effect of galectin-3 involves the interaction of galectin-3 with integrins or glycans expressed on cell surface molecules [52]. This causes clustering of galectin-3 with its cell surface ligands and the activation of focal adhesion kinase that leads to modulation of vascular endothelial growth factor (VEGF)- and basic fibroblast growth factor (bFGF)-mediated angiogenesis [53]. An interaction of galectin-3 with the endothelial cell surface enzyme aminopeptidase N/CD13 has also been reported to regulate endothelial vascularisation in the early steps of angiogenesis [54]. 1.7. Galectin-3 in cancer cell adhesion Tumour cell adhesion to and subsequent invasion through the extracellular matrix (ECM) at primary tumour sites are essential steps in epithelial cancer metastasis. Galectin-3 overexpression is associated with an increased invasiveness of many types of tumour cells such as neuroendocrine tumour pheochromocytoma, ovarian, melanoma, thyroid and colorectal cancer cells [4,55]. Overexpression of galectin-3 enhances tumour cell adhesion to ECM and promotes the escape of tumour cells from the primary tumour sites [37]. Such an effect of galectin-3 is attributed partly by its interaction with a range of the ECM glycoproteins such as fibronectins, collagen IV, elastin, and laminin [4]. The interaction of galectin-3 with cancer cell surface glycans such as the Mgat5-modified N-glycans [56], laminin and lysosome-associated membrane glycoproteins [4,55] has also shown to be involved in galectin-3-mediated cancer cell adhesion. The interaction of galectin-3 with cell surface epidermal growth factor receptor (EGFR) and transforming growth factor-b receptor (TGFbR) is believed to also contribute to the increased invasiveness of tumour cells. In this case, galectin-3 crosslinks these cell surface molecules and prevent their endocytosis and signalling. 1.8. Galectin-3 in tumour cell metastatic spreading Survival of the invaded tumour cells in the blood/lymphatic circulation and their subsequent adhesion to the blood vascular endothelium composes of important steps in cancer metastasis. Recent investigations have revealed that circulating galectin-3 may play a very important role in these processes [57]. Compared with that in healthy people, the level of circulating galectin-3 is significantly higher in the bloodstream of cancer patients in particular those with metastasis [58]. Higher level of circulating galectin-3 is associated with increased metastasis and poor prognosis in several types of cancers including colorectal, thyroid and ovarian cancer. It has been demonstrated recently that galectin-3 binds to the oncofoetal ThomsenFriedenreich (galactoseb1,3 N-acetylgalactosaminea, TF)
antigen on the transmembrane mucin MUC1 expressed on tumour cells [59]. The binding of galectin-3 to cancerassociated TF/MUC1 induces redistribution of MUC1 on the cell surface that allows the exposure of the smaller cell surface adhesion molecules which otherwise are concealed by the large and heavily glycosylated cell surface MUC1. This results in increased cancer cell heterotypic adhesion to the blood vascular endothelium [60] as well as increased cancer cell homotypic aggregation for the formation of tumour micro-emboli [61]. The formation of tumour microemboli enhances the survival of disseminating tumour cells in the circulation by preventing initiation of anoikis. Moreover, galectin-3 expressed on cancer as well as on endothelial cell surface can itself act as a cell adhesion molecule by interaction with the cancer- and endothelialassociated TF disaccharides and increase cancer cell heterotypic adhesion to vascular endothelium and cancer cell homotypic aggregation in cancer cell haematogenous dissemination in metastasis [62–64]. 2. Conclusion remarks As a multifunctional protein widely expressed by many types of human cells, galectin-3 overexpression and changes of sub- and inter-cellular localization are commonly seen in various types of human cancers. Although much remains to be further explored, more and more evidence indicates that galectin-3 is involved in the regulations of a myriad of cancer cell activities during cancer development, progression and metastasis. This is hugely attributed to the altered interactions of galectin-3 with a range of different binding partners at different locations in cancer conditions. Targeting the actions of galectin-3 will represent a promising therapeutic strategy for the development of effective therapeutic agents for cancer treatment. Acknowledgments The work in the authors’ laboratory was supported by Cancer Research UK Grant C7596 (to LGY) and North West Cancer Research Fund Grant CR777 (to LGY). References [1] S.H. Barondes, D.N. Cooper, M.A. Gitt, H. Leffler, Galectins. Structure and function of a large family of animal lectins, J. Biol. Chem. 269 (1994) 20807–20810. [2] R.Y. Yang, G.A. Rabinovich, F.T. Liu, Galectins: structure, function and therapeutic potential, Expert. Rev. Mol. Med. 10 (2008) e17. [3] M.K. Ho, T.A. Springer, Mac-2, a novel 32, 000 Mr mouse macrophage subpopulation-specific antigen defined by monoclonal antibodies, J. Immunol. 128 (1982) 1221–1228. [4] J. Dumic, S. Dabelic, M. Flogel, Galectin-3: an open-ended story, Biochim. Biophys. Acta 1760 (2006) 616–635. [5] B. Birdsall, J. Feeney, I.D. Burdett, S. Bawumia, E.A. Barboni, R.C. Hughes, NMR solution studies of hamster galectin-3 and electron microscopic visualization of surface-adsorbed complexes: evidence for interactions between the N- and C-terminal domains, Biochemistry 40 (2001) 4859–4866. [6] A. Raz, G. Pazerini, P. Carmi, Identification of the metastasisassociated, galactoside-binding lectin as a chimeric gene product with homology to an IgE-binding protein, Cancer Res. 49 (1989) 3489–3493.
A.U. Newlaczyl, L.-G. Yu / Cancer Letters 313 (2011) 123–128 [7] D. Houzelstein, I.R. Goncalves, A.J. Fadden, S.S. Sidhu, D.N. Cooper, K. Drickamer, H. Leffler, F. Poirier, Phylogenetic analysis of the vertebrate galectin family, Mol. Biol. Evol. 21 (2004) 1177–1187. [8] S.M. Massa, D.N. Cooper, H. Leffler, S.H. Barondes, L-29, an endogenous lectin, binds to glycoconjugate ligands with positive cooperativity, Biochemistry 32 (1993) 260–267. [9] J. Ochieng, B. Green, S. Evans, O. James, P. Warfield, Modulation of the biological functions of galectin-3 by matrix metalloproteinases, Biochim. Biophys. Acta 1379 (1998) 97–106. [10] H.C. Gong, Y. Honjo, P. Nangia-Makker, V. Hogan, N. Mazurak, R.S. Bresalier, A. Raz, The NH2 terminus of galectin-3 governs cellular compartmentalization and functions in cancer cells, Cancer Res. 59 (1999) 6239–6245. [11] R.P. Menon, R.C. Hughes, Determinants in the N-terminal domains of galectin-3 for secretion by a novel pathway circumventing the endoplasmic reticulum-Golgi complex, Eur. J. Biochem. 264 (1999) 569–576. [12] T. Yoshii, T. Fukumori, Y. Honjo, H. Inohara, H.R. Kim, A. Raz, Galectin-3 phosphorylation is required for its anti-apoptotic function and cell cycle arrest, J. Biol. Chem. 277 (2002) 6852–6857. [13] J. Seetharaman, A. Kanigsberg, R. Slaaby, H. Leffler, S.H. Barondes, J.M. Rini, X-ray crystal structure of the human galectin-3 carbohydrate recognition domain at 2.1-A resolution, J. Biol. Chem. 273 (1998) 13047–13052. [14] E.A. Barboni, S. Bawumia, K. Henrick, R.C. Hughes, Molecular modeling and mutagenesis studies of the N-terminal domains of galectin-3: evidence for participation with the C-terminal carbohydrate recognition domain in oligosaccharide binding, Glycobiology 10 (2000) 1201–1208. [15] S. Akahani, P. Nangia-Makker, H. Inohara, H.R. Kim, A. Raz, Galectin3: a novel antiapoptotic molecule with a functional BH1 (NWGR) domain of Bcl-2 family, Cancer Res. 57 (1997) 5272–5276. [16] C. Colnot, D. Fowlis, M.A. Ripoche, I. Bouchaert, F. Poirier, Embryonic implantation in galectin 1/galectin 3 double mutant mice, Dev. Dyn. 211 (1998) 306–313. [17] R.Y. Yang, D.K. Hsu, F.T. Liu, Expression of galectin-3 modulates T-cell growth and apoptosis, Proc. Natl. Acad. Sci. USA 93 (1996) 6737–6742. [18] N. Agrwal, Q. Sun, S.Y. Wang, J.L. Wang, Carbohydrate-binding protein 35. I: Properties of the recombinant polypeptide and the individuality of the domains, J. Biol. Chem. 268 (1993) 14932– 14939. [19] S. Sato, R.C. Hughes, Binding specificity of a baby hamster kidney lectin for H type I and II chains, polylactosamine glycans, and appropriately glycosylated forms of laminin and fibronectin, J. Biol. Chem. 267 (1992) 6983–6990. [20] J. Hirabayashi, T. Hashidate, Y. Arata, N. Nishi, T. Nakamura, M. Hirashima, T. Urashima, T. Oka, M. Futai, W.E. Muller, F. Yagi, K. Kasai, Oligosaccharide specificity of galectins: a search by frontal affinity chromatography, Biochim. Biophys. Acta 1572 (2002) 232–254. [21] G. Elad-Sfadia, R. Haklai, E. Balan, Y. Kloog, Galectin-3 augments KRas activation and triggers a Ras signal that attenuates ERK but not phosphoinositide 3-kinase activity, J. Biol. Chem. 279 (2004) 34922– 34930. [22] R.P. Menon, M. Strom, R.C. Hughes, Interaction of a novel cysteine and histidine-rich cytoplasmic protein with galectin-3 in a carbohydrate-independent manner, FEBS Lett. 470 (2000) 227–231. [23] I. Paron, A. Scaloni, A. Pines, A. Bachi, F.T. Liu, C. Puppin, M. Pandolfi, L. Ledda, C. Di Loreto, G. Damante, G. Tell, Nuclear localization of Galectin-3 in transformed thyroid cells: a role in transcriptional regulation, Biochem. Biophys. Res. Commun. 302 (2003) 545–553. [24] T. Shimura, Y. Takenaka, T. Fukumori, S. Tsutsumi, K. Okada, V. Hogan, A. Kikuchi, H. Kuwano, A. Raz, Implication of galectin-3 in Wnt signaling, Cancer Res. 65 (2005) 3535–3537. [25] T. Shimura, Y. Takenaka, S. Tsutsumi, V. Hogan, A. Kikuchi, A. Raz, Galectin-3, a novel binding partner of beta-catenin, Cancer Res. 64 (2004) 6363–6367. [26] R.C. Hughes, Secretion of the galectin family of mammalian carbohydrate-binding proteins, Biochim. Biophys. Acta 1473 (1999) 172–185. [27] J.C. Gaudin, B. Mehul, R.C. Hughes, Nuclear localisation of wild type and mutant galectin-3 in transfected cells, Biol. Cell 92 (2000) 49–58. [28] Y.G. Tsay, N.Y. Lin, P.G. Voss, R.J. Patterson, J.L. Wang, Export of galectin-3 from nuclei of digitonin-permeabilized mouse 3T3 fibroblasts, Exp. Cell Res. 252 (1999) 250–261. [29] R. Shalom-Feuerstein, T. Cooks, A. Raz, Y. Kloog, Galectin-3 regulates a molecular switch from N-Ras to K-Ras usage in human breast carcinoma cells, Cancer Res. 65 (2005) 7292–7300.
127
[30] Y.J. Lee, Y.K. Song, J.J. Song, R.R. Siervo-Sassi, H.R. Kim, L. Li, D.R. Spitz, A. Lokshin, J.H. Kim, Reconstitution of galectin-3 alters glutathione content and potentiates TRAIL-induced cytotoxicity by dephosphorylation of Akt, Exp. Cell Res. 288 (2003) 21–34. [31] N. Oka, S. Nakahara, Y. Takenaka, T. Fukumori, V. Hogan, H.O. Kanayama, T. Yanagawa, A. Raz, Galectin-3 inhibits tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by activating Akt in human bladder carcinoma cells, Cancer Res. 65 (2005) 7546–7553. [32] S. Morris, N. Ahmad, S. Andre, H. Kaltner, H.J. Gabius, M. Brenowitz, F. Brewer, Quaternary solution structures of galectins-1, -3, and -7, Glycobiology 14 (2004) 293–300. [33] R.Y. Yang, P.N. Hill, D.K. Hsu, F.T. Liu, Role of the carboxyl-terminal lectin domain in self-association of galectin-3, Biochemistry 37 (1998) 4086–4092. [34] N. Ahmad, H.J. Gabius, S. Andre, H. Kaltner, S. Sabesan, R. Roy, B. Liu, F. Macaluso, C.F. Brewer, Galectin-3 precipitates as a pentamer with synthetic multivalent carbohydrates and forms heterogeneous cross-linked complexes, J. Biol. Chem. 279 (2004) 10841–10847. [35] C.F. Brewer, M.C. Miceli, L.G. Baum, Clusters, bundles, arrays and lattices: novel mechanisms for lectin-saccharide-mediated cellular interactions, Curr. Opin. Struct. Biol. 12 (2002) 616–623. [36] F.T. Liu, G.A. Rabinovich, Galectins as modulators of tumour progression, Nat. Rev. Cancer 5 (2005) 29–41. [37] J. Ochieng, V. Furtak, P. Lukyanov, Extracellular functions of galectin3, Glycoconj J. 19 (2004) 527–535. [38] R.C. Hughes, The galectin family of mammalian carbohydratebinding molecules, Biochem. Soc. Trans. 25 (1997) 1194–1198. [39] S. Andre, S. Kojima, N. Yamazaki, C. Fink, H. Kaltner, K. Kayser, H.J. Gabius, Galectins-1 and -3 and their ligands in tumor biology. Non-uniform properties in cell-surface presentation and modulation of adhesion to matrix glycoproteins for various tumor cell lines, in biodistribution of free and liposome-bound galectins and in their expression by breast and colorectal carcinomas with/ without metastatic propensity, J. Cancer Res. Clin. Oncol. 125 (1999) 461–474. [40] X. Sanjuan, P.L. Fernandez, A. Castells, V. Castronovo, F. van den Brule, F.T. Liu, A. Cardesa, E. Campo, Differential expression of galectin 3 and galectin 1 in colorectal cancer progression, Gastroenterology 113 (1997) 1906–1915. [41] Y. Honjo, P. Nangia-Makker, H. Inohara, A. Raz, Down-regulation of galectin-3 suppresses tumorigenicity of human breast carcinoma cells, Clin. Cancer Res. 7 (2001) 661–668. [42] T. Yoshii, H. Inohara, Y. Takenaka, Y. Honjo, S. Akahani, T. Nomura, A. Raz, T. Kubo, Galectin-3 maintains the transformed phenotype of thyroid papillary carcinoma cells, Int. J. Oncol. 18 (2001) 787– 792. [43] Y. Takenaka, H. Inohara, T. Yoshii, K. Oshima, S. Nakahara, S. Akahani, Y. Honjo, Y. Yamamoto, A. Raz, T. Kubo, Malignant transformation of thyroid follicular cells by galectin-3, Cancer Lett. 195 (2003) 111–119. [44] F. Yu, R.L. Finley Jr., A. Raz, H.R. Kim, Galectin-3 translocates to the perinuclear membranes and inhibits cytochrome c release from the mitochondria. A role for synexin in galectin-3 translocation, J. Biol. Chem. 277 (2002) 15819–15827. [45] P. Matarrese, N. Tinari, M.L. Semeraro, C. Natoli, S. Iacobelli, W. Malorni, Galectin-3 overexpression protects from cell damage and death by influencing mitochondrial homeostasis, FEBS Lett. 473 (2000) 311–315. [46] S. Califice, V. Castronovo, M. Bracke, F. van den Brule, Dual activities of galectin-3 in human prostate cancer: tumor suppression of nuclear galectin-3 vs tumor promotion of cytoplasmic galectin-3, Oncogene 23 (2004) 7527–7536. [47] L. Liu, T. Sakai, N. Sano, K. Fukui, Nucling mediates apoptosis by inhibiting expression of galectin-3 through interference with nuclear factor kappaB signalling, Biochem. J. 380 (2004) 31–41. [48] G.C. Fernandez, J.M. Ilarregui, C.J. Rubel, M.A. Toscano, S.A. Gomez, M. Beigier Bompadre, M.A. Isturiz, G.A. Rabinovich, M.S. Palermo, Galectin-3 and soluble fibrinogen act in concert to modulate neutrophil activation and survival: involvement of alternative MAPK pathways, Glycobiology 15 (2005) 519–527. [49] E. Feuk-Lagerstedt, E.T. Jordan, H. Leffler, C. Dahlgren, A. Karlsson, Identification of CD66a and CD66b as the major galectin-3 receptor candidates in human neutrophils, J. Immunol. 163 (1999) 5592– 5598. [50] H. Sano, D.K. Hsu, L. Yu, J.R. Apgar, I. Kuwabara, T. Yamanaka, M. Hirashima, F.T. Liu, Human galectin-3 is a novel chemoattractant for monocytes and macrophages, J. Immunol. 165 (2000) 2156– 2164.
128
A.U. Newlaczyl, L.-G. Yu / Cancer Letters 313 (2011) 123–128
[51] P. Nangia-Makker, Y. Honjo, R. Sarvis, S. Akahani, V. Hogan, K.J. Pienta, A. Raz, Galectin-3 induces endothelial cell morphogenesis and angiogenesis, Am. J. Pathol. 156 (2000) 899–909. [52] J. Fukushi, I.T. Makagiansar, W.B. Stallcup, NG2 proteoglycan promotes endothelial cell motility and angiogenesis via engagement of galectin-3 and alpha3beta1 integrin, Mol. Biol. Cell 15 (2004) 3580–3590. [53] A.I. Markowska, F.T. Liu, N. Panjwani, Galectin-3 is an important mediator of VEGF- and bFGF-mediated angiogenic response, J. Exp. Med. 207 (2010) 1981–1993. [54] E. Yang, J.S. Shim, H.J. Woo, K.W. Kim, H.J. Kwon, Aminopeptidase N/ CD13 induces angiogenesis through interaction with a proangiogenic protein, galectin-3, Biochem. Biophys. Res. Commun. 363 (2007) 336–341. [55] H. Barrow, J.M. Rhodes, L.-G. Yu, The role of galectins in colorectal cancer progression, Int. J. Cancer 129 (2011) 1–8. [56] A. Lagana, J.G. Goetz, P. Cheung, A. Raz, J.W. Dennis, I.R. Nabi, Galectin binding to Mgat5-modified N-glycans regulates fibronectin matrix remodeling in tumor cells, Mol. Cell Biol. 26 (2006) 3181–3193. [57] L.G. Yu, Circulating galectin-3 in the bloodstream: An emerging promoter of cancer metastasis, World J. Gastrointest Oncol. 2 (2010) 177–180. [58] I. Iurisci, N. Tinari, C. Natoli, D. Angelucci, E. Cianchetti, S. Iacobelli, Concentrations of galectin-3 in the sera of normal controls and cancer patients, Clin. Cancer Res. 6 (2000) 1389–1393.
[59] L.G. Yu, N. Andrews, Q. Zhao, D. McKean, J.F. Williams, L.J. Connor, O.V. Gerasimenko, J. Hilkens, J. Hirabayashi, K. Kasai, J.M. Rhodes, Galectin-3 interaction with Thomsen-Friedenreich disaccharide on cancer-associated MUC1 causes increased cancer cell endothelial adhesion, J. Biol. Chem. 282 (2007) 773–781. [60] Q. Zhao, X. Guo, G.B. Nash, P.C. Stone, J. Hilkens, J.M. Rhodes, L.G. Yu, Circulating galectin-3 promotes metastasis by modifying MUC1 localization on cancer cell surface, Cancer Res. 69 (2009) 6799–6806. [61] Q. Zhao, M. Barclay, J. Hilkens, X. Guo, H. Barrow, J.M. Rhodes, L.G. Yu, Interaction between circulating galectin-3 and cancer-associated MUC1 enhances tumour cell homotypic aggregation and prevents anoikis, Mol. Cancer 9 (2010) 154. [62] J. Zou, V.V. Glinsky, L.A. Landon, L. Matthews, S.L. Deutscher, Peptides specific to the galectin-3 carbohydrate recognition domain inhibit metastasis-associated cancer cell adhesion, Carcinogenesis 26 (2005) 309–318. [63] V.V. Glinsky, G.V. Glinsky, K. Rittenhouse-Olson, M.E. Huflejt, O.V. Glinskii, S.L. Deutscher, T.P. Quinn, The role of ThomsenFriedenreich antigen in adhesion of human breast and prostate cancer cells to the endothelium, Cancer Res. 61 (2001) 4851–4857. [64] S.K. Khaldoyanidi, V.V. Glinsky, L. Sikora, A.B. Glinskii, V.V. Mossine, T.P. Quinn, G.V. Glinsky, P. Sriramarao, MDA-MB-435 human breast carcinoma cell homo- and heterotypic adhesion under flow conditions is mediated in part by Thomsen-Friedenreich antigengalectin-3 interactions, J. Biol. Chem. 278 (2003) 4127–4134.