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Class III β-tubulin in normal and cancer tissues
Gene 563 (2015) 109–114
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Class III β-tubulin in normal and cancer tissues Marisa Mariani, Roshan Karki, Manuela Spennato, Deep Pandya, Shiquan He, Mirko Andreoli, Paul Fiedler, Cristiano Ferlini ⁎ Danbury Hospital Research Institute, Danbury, CT, USA
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Article history: Received 3 December 2014 Received in revised form 26 March 2015 Accepted 27 March 2015 Available online 1 April 2015 Keywords: βIII-Tubulin TUBB3 Biomarker Neural differentiation Cancer
a b s t r a c t Microtubules are polymeric structures composed of tubulin subunits. Each subunit consists of a heterodimer of α- and β-tubulin. At least seven β-tubulin isotypes, or classes, have been identified in human cells, and constitutive isotype expression appears to be tissue specific. Class III β-tubulin (βIII-tubulin) expression is normally confined to testes and tissues derived from neural cristae. However, its expression can be induced in other tissues, both normal and neoplastic, subjected to a toxic microenvironment characterized by hypoxia and poor nutrient supply. In this review, we will summarize the mechanisms underlying βIII-tubulin constitutive and induced expression. We will also illustrate its capacity to serve as a biomarker of neural commitment in normal tissues and as a pure prognostic biomarker in cancer patients. © 2015 Elsevier B.V. All rights reserved.
1. βIII-Tubulin and the microtubules Microtubules are filamentous, cytoskeletal polymers found in all eukaryotes and are involved in critical cellular processes such as mitosis, cell motility, and intracellular transport. The core cylinders of microtubules are composed of basic building blocks, α- and β-tubulin monomers, that spontaneously assemble to form functional subunits called heterodimers. These α/β heterodimers polymerize in a linear fashion to form “head to tail” polar protofilaments with β-tubulin facing headwards and α-tubulin oriented toward the tails. Along with the head to tail interaction, heterodimers interact also laterally to form the cylinder that is the microtubule. Although the term “cytoskeletal” may imply stasis and permanence, microtubules are in fact highly dynamic and ethereal. The vibrant kinetics of microtubule assembly and disassembly are self-regulated at least in part by β-tubulins, which are not only structural proteins but GTPases as well. As critical yet ever-changing components of cell function, microtubules are often targeted when designing novel therapeutics and pharmaceuticals (Jordan and Kamath, 2007). Multiple genes encode α- and β-tubulin isotypes. These genes show high homology (Ferlini et al., 2007) and conservation across vertebrate species (Tuszynski et al., 2006) indicating origins from a common Abbreviations: βIII-Tubulin, class III β-tubulin; MAP, microtubule associated proteins; ABC, ATP binding cassette; UTR, untranslated region; CFEOM3, congenital fibrosis of extraocular muscles 3; GBP-1, guanylate-binding protein 1; PIM-1, proviral integration site 1; HIF-1α, hypoxia inducible factor 1α; HIF-2α, hypoxia inducible factor 2α. ⁎ Corresponding author at: Danbury Hospital Research Institute, 131 West Street, Danbury, CT, USA. E-mail address: [email protected] (C. Ferlini).
http://dx.doi.org/10.1016/j.gene.2015.03.061 0378-1119/© 2015 Elsevier B.V. All rights reserved.
ancestral gene. Both α- and β-tubulin isotypes, like cytokeratin isotypes, demonstrate differential tissue expression patterns during embryogenesis, suggesting diversity in functionality and a specific role in the differentiation processes (Sullivan and Cleveland, 1986). At least seven β-tubulin isotypes have been identified in the human genome (Ferlini et al., 2007). These vary in the final 15 C-terminus residues which are exposed for the interaction with microtubule associated proteins (MAPs). They also differ in the composition of the 3′-UTR flanking region implicated in transcriptional and translational regulation. These modifications confer properties which match the metabolic and structural needs of a given tissue. βIII-Tubulin is encoded by the TUBB3 gene which firstly appeared in fish, both osteoichthyes and chondrichthyes (Tuszynski et al., 2006; Joe et al., 2008), thus coinciding with the time of vertebrate evolution and exposure to the higher tension of oxygen (Towe, 1970). βIII-Tubulin is constitutively expressed in the central and peripheral nervous systems and in the testes, specifically in Sertoli cells. In in vitro cultured cancer cells, constitutive TUBB3 expression seems regulated in a cell-cycle dependent way, with maximal expression at the G2/M phase of the cell cycle (Shibazaki et al., 2012). Such constitutive expression is linked to the expression levels of the RE1-silencing transcription factor (REST). REST binds to the first TUBB3 exon and suppresses the constitutive TUBB3 expression (Gao et al., 2012). In other tissues, both normal and neoplastic, the expression of βIIItubulin is induced by exposure to a toxic microenvironment featured by hypoxia and poor nutrient supply. In this review, we will describe the regulation of TUBB3 in humans and its functional role in normal and diseased tissues. We will also
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Fig. 1. Representative multiplexed fluorescent immunohistochemistry of a high grade serous ovarian cancer case stained with anti-TUBB3. In blue — cell nuclei stained with DAPI; in green — stromal cells stained with anti-vimentin; in yellow — epithelial cancer cells stained with anti-cytokeratin; in pink — TUBB3 expression stained with anti-TUBB3 (clone TUJ1). The TUJ1 pattern of staining is cytoplasmic and as in this case is often heterogeneous within the cancer cell population in high grade serous ovarian.
provide a context for understanding why βIII-tubulin has been extensively documented as a biomarker of poor outcome in a panel of solid malignancies. 2. Gene structure of human TUBB3 The human TUBB3 gene is located on chromosome 16q24.3 and consists of 4 exons that transcribe a protein of 450 aa. A shorter isoform of 378 aa derived from the alternative splicing of exon 1 is devoid of a part of the N-terminus and may be responsible for mitochondrial expression (Andre et al., 2000; Cicchillitti et al., 2008), whose functional significance remains unknown. Similar to other β-tubulin isotypes, βIII-tubulin has a GTPase domain which is essential in regulating microtubule dynamics (Katsetos and Draber, 2012). Class I (the most represented and constitutively expressed isotype) and βIII-tubulin differ by just 13 aa within the 1–429 aa region, whereas region 430–450 aa is completely divergent. These variations in the primary structure affect the paclitaxel binding domain (Ferlini et al., 2005, 2007; Magnani et al., 2006) on βIII-tubulin and may account for the ability of this isotype to confer resistance to paclitaxel initiated apoptosis (Ferlini et al., 2009). Since paclitaxel is a Nur-77 mimic, βIII-tubulin may represent the inherent survival pathway to Nur-77 induced cell death (Ferlini et al., 2009). In fact, Nur-77 translocation from the nucleus to mitochondria activates a cell death program (Lin et al., 2004), which is inhibited by βIII-tubulin expression (Ferlini et al., 2009). 3. Expression and function of βIII-tubulin A recent PUBMED search using keywords “class III β-tubulin” or “TUBB3” retrieved 610 references. Of these, 51% (309/610) relate to its role in neural differentiation. The knowledge of TUBB3 as a neuronal marker dates back to 1989 when the first monoclonal anti-class III βtubulin antibody (TUJ1) became available (Caccamo et al., 1989). The expression of βIII-tubulin by medulloepithelial rosettes suggested that this isotype was one of the earliest markers to signal neuronal commitment in primitive human neuroepithelium. This hypothesis was later confirmed in other species (Lee et al., 1990; Linhartova et al., 1992). The critical importance of the TUBB3 gene in neural development has also been confirmed by the study of TUBB3 mutations in congenital syndromes. A panel of at least eight heterozygous missense mutations was shown to produce congenital fibrosis of extraocular muscles 3 (CFEOM3), a group of eye movement disorders caused by the dysfunction of the oculomotor nerve (Tischfield et al., 2010). The classical CFEOM3 symptoms, ptosis and restricted eye movements, are observed
at birth. These symptoms are associated with additional nervous system disorders. CFEOM3 patients exhibit peripheral axonal neuropathy, facial paralysis, and often intellectual and behavioral impairments. Conventional neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerves along with dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. The commonest TUBB3 mutation causing CFEOM3 results in a R262C amino acid substitution. A TUBB3R262C knock-in mouse model reveals axon guidance defects of the oculomotor nerve and central axon tracts without evidence of cortical cell migration abnormalities (Tischfield et al., 2010). By contrast, six other diverse missense mutations in the TUBB3 gene were observed in patients with cortical disorganization and axonal abnormalities associated with pontocerebellar hypoplasia but without ocular motility defects typical of CFEOM3 (Poirier et al., 2010). The diverse spectra of phenotypic changes related to congenital TUBB3 mutations highlights the pivotal role this protein plays in neuronal development. As further evidence of its specificity, TUBB3 inactivation impairs neural progenitor proliferation which cannot be rescued or restored by other β-tubulins (Saillour et al., 2014). TUBB3 expression is also constitutively expressed in the testis where it is regulated by androgen exposure during ontogenesis in mouse and rat Sertoli cells (De Gendt et al., 2011). Hormonal influence of TUBB3 expression has also been identified in neoplasia. Breast carcinoma cells, for example, show TUBB3 under the control of estradiol via the estrogen receptor (Saussede-Aim et al., 2009). In prostate cancer, βIIItubulin expression is strongly associated with both TMPRSS2:ERG rearrangement, ERG expression and PTEN deletions, three key oncogenetic features of aggressive prostate cancer (Tsourlakis et al., 2014). Also, colorectal cancer is more aggressive in young male patients in whom testosterone elevation and activation of TUBB3 are connected with poor outcome (Shahabi et al., 2013; Orsted et al., 2014). 4. βIII-Tubulin and taxane-resistance: a need for critical revision? The primary interest in βIII-tubulin in oncology relates to its putative role in taxane-resistance. Large metanalyses (Reiman et al., 2012) and a number of additional smaller studies (Ferrandina et al., 2007; Urano et al., 2006; Ohishi et al., 2007; Umezu et al., 2008; Terry et al., 2009; Ishida et al., 2009; Hayashi et al., 2009; Azuma et al., 2009; Yoon et al., 2010; Ploussard et al., 2010; Miyamoto et al., 2010; Koh et al., 2010; Mariani et al., 2012; Leskela et al., 2011; Hirai et al., 2011; Levallet et al., 2012; Zhang et al., 2012; Vilmar et al., 2012; Roque et al., 2014) have clearly indicated that βIII-tubulin is linked to poor outcome (See Fig. 1.). Taxanes inhibit tubulin depolymerization thereby increasing
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intracellular levels of polymerized tubulin and arresting cellular functions. Early pivotal in vitro studies demonstrated that different proportions of tubulin isotypes affect microtubule dynamics. In particular, βIII-tubulin was shown to enhance the rate of tubulin depolymerization (Panda et al., 1994), a feature that could account for resistance to taxanes, drugs that promote tubulin assembly. Indeed, a number of early studies of ovarian (Kavallaris et al., 1997; Mozzetti et al., 2005) and lung (Seve et al., 2005) carcinomas supported this notion. However, this direct correlation was challenged by subsequent findings. For example, when βIII-tubulin was moderately expressed under a conditional promoter, there was only a weak induction (less than twofold) of paclitaxelresistance (Hari et al., 2003). Furthermore, increased expression of βIIItubulin was documented in patients treated with drugs acting as direct inhibitors of tubulin polymerization such as Vinca alkaloids (Seve et al., 2007). Even more problematic, in breast cancer (Galmarini et al., 2008; Wang et al., 2013), clear cell ovarian carcinoma (Aoki et al., 2009) and melanoma (Akasaka et al., 2009), studies have reported that high expression of βIII-tubulin was linked to sensitivity to taxane-based chemotherapy and not resistance. In this sense, in tissues where constitutive βIII-tubulin is present, low expression of this tubulin isotype is a sign of de-differentiation and more aggressive disease. As an apparent paradox, in tissues where constitutive βIII-tubulin is absent, its aberrant expression is associated in most cases, but not always, with an aggressive phenotype regardless if the disease is treated with a taxane or not (Katsetos and Draber, 2012; Akasaka et al., 2009; Katsetos et al., 2003a,b; Caracciolo et al., 2010; Katsetos et al., 2011; Karki et al., 2013). Postulating that βIII-tubulin alone regulates microtubule dynamics and induces resistance to taxanes is clearly an over-simplification. In fact, many factors are capable of binding to βIII-tubulin, such as γtubulin (Katsetos et al., 2007, 2009), SEMA6A (Prislei et al., 2008), GBP-1 (De Donato et al., 2012) and Erp57 (Cicchillitti et al., 2008). Moreover, TUBB3 expression can occur in concert with other elements, when transcription is activated by exposure to a toxic microenvironment featured by low oxygen (Raspaglio et al., 2008, 2014) and poor nutrient supply (Raspaglio et al., 2010). In the 3′ flanking region of TUBB3, there is an E-box (5′-RCGTG-3) which binds hypoxia induced transcription factors, HIF-1α and -2α. Accordingly, βIII-tubulin staining appears in hypoxic areas within tumors (Katsetos et al., 2001). Hypoxia triggers pro-survival pathways (Raspaglio et al., 2003; McCarroll et al., 2015) rendering cells resistant to taxanes along with a number of other drugs. In this context, βIII-tubulin is not a passive bystander. In cell lines with an aggressive phenotype and constitutive βIII-tubulin expression, βIII-tubulin knockdown is associated with reduced growth and increased chemotherapy sensitivity when compared with control clones (Gan et al., 2007; McCarroll et al., 2010). β-tubulins are redoxcontrolled proteins. As such, they have cysteine residues that can be reversibly oxidized resulting in the modification of protein function (Barford, 2004). Khan and Luduena have proposed that oxidative stress and the thioredoxin system regulate the dimer/microtubule equilibrium (Khan and Luduena, 1991). Proteomic analysis has revealed that many factors that bind to βIII-tubulin are involved in the oxidative stress and glucose deprivation response (Cicchillitti et al., 2008). In structural terms, constitutive Class I (TUBB) and Class IVb (TUBB2C) β-tubulins contain a cysteine at position 239, while βIII-tubulin has a cysteine at position 124. Position 239 can be readily oxidized while position 124 is relatively resistant to oxidation (Joe et al., 2008). Thus, a relative abundance of βIII-tubulin in situations of oxidative stress should enhance pro-survival signals and cell integrity (De Donato et al., 2012). This concept appears especially plausible in light of the fact that, as mentioned above, βIII-tubulin first appears in evolutionary history at the time of increased exposure to oxygen. Among the components of the cytoskeletal gateway to resistance, a leading role is played by the GBP-1 (guanylate-binding protein 1) GTPase. This enzyme directly binds to βIII-tubulin and facilitates the incorporation of a panel of pro-survival factors into the cytoskeleton including PIM-1 (Proviral Integration Site 1) and another 19 kinases (De Donato et al.,
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2012). Integrated analysis of GBP-1 along with upstream βIII-tubulin regulators (HIF-1α and -2α, miR-200c) and downstream effectors of βIII-tubulin enables accurate identification of a subset of cancer patients in whom the aggressive pathway is activated (De Donato et al., 2012; Raspaglio et al., 2014; Prislei et al., 2013). In functional terms, the expression of βIII-tubulin in normal tissues seems to be finalized to the protection of the most precious progenitors in tissues. This phenomenon seems not specific of the neural progenitors (Draberova et al., 2008; Petschnik et al., 2011; Foudah et al., 2014). In this sense, βIII-tubulin could be considered as a marker of stemness. Also within cancer tissues, βIII-tubulin expression may simply indicate an enrichment of cancer stem-like cells (Moitra et al., 2011; Li et al., 2014), featured by certain ABC transporters such as ABCB1 (known as Pgp/MDR1), ABCG2 (known as BCRP) and very efficient systems of DNA repair. The coordinate expression of multiple factors aimed at the stem cell protection from xenobiotics may then cause the multidrug resistance phenotype responsible for poor response to chemotherapy in patients. In summary, βIII-tubulin is not a predictive biomarker of taxaneresistance. Instead, βIII-tubulin is a pure prognostic biomarker only when its expression is conditioned by a toxic microenvironment. However, when its expression is driven by other factors, the βIIItubulin role is neutral or even opposite, acting as a marker of a more differentiated and less aggressive disease. 5. βIII-Tubulin as a drug target Since the discovery of βIII-tubulin's role in drug-resistance, a number of strategies have been pursued to inhibit its function. An early approach consisted of high throughput screening of cells over-expressing βIIItubulin with novel anti-tubulin agents. This strategy led to the synthesis of IDN5390 (Ferlini et al., 2005) and other seco-taxanes (Pepe et al., 2009). These drugs were designed in silico through computational modeling of the paclitaxel binding domain of βIII-tubulin, which is slightly different from that of class I, the most expressed β-tubulin isotype. For the fact that βIII-tubulin and the ABCB1 efflux pump are co-expressed in the same cancer stem-like cells, it is not surprising that drugs particularly active against βIII-tubulin are not a substrate of ABCB1 and produce cytotoxic effects in multidrug resistant cell lines (Ferlini et al., 2005; Pepe et al., 2009; Cai et al., 2013; Mozzetti et al., 2008). In silico modeling provided additional insights into the potential mechanisms of βIII-tubulin inhibition. Through this analysis, epothilones, particularly, patupilone (Epothilone-B), were proposed as promising agents, a promise that was borne out when patupilone-resistant ovarian and endometrial cancer cells exhibited significant down-regulation of TUBB3 (Mozzetti et al., 2008; Carrara et al., 2012). Although patupilone is known to produce a dramatic therapeutic response in a subset of patients (Ferrandina et al., 2012), a large multicenter ovarian cancer study of this agent failed to obtain its primary endpoint (Colombo et al., 2012). We suggest that the lack of inclusion of βIII-tubulin expression as a criterion of enrollment contributed to this failure. The ex-novo creation of novel βIII-tubulin inhibitors is hampered by the absence of a simple, reliable in vitro test of βIII-tubulin function. To be active, βIII-tubulin requires dimerization, assembly in polymeric structures with additional cytoskeletal elements including MAP, and other post-translational changes which cannot be readily reproduced in vitro. An alternative strategy leverages the knowledge that βIIItubulin function is mediated through GBP-1. Unlike βIII-tubulin, GBP-1 can be expressed in vitro in an active form and its downstream interactions with prosurvival kinases such as PIM-1 (De Donato et al., 2012; Persico et al., 2015) can be quantified in response to various compounds of interest. This approach led to the identification of aza-podophyllotoxin as a potential therapeutic inhibitor of βIII-tubulin prosurvival function (Andreoli et al., 2014). Noteworthy, podophyllotoxin is a known inhibitor of tubulin polymerization and a competitive antagonist of the colchicine binding site (Loike and
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Horwitz, 1976; Cortese et al., 1977). As demonstrated by the case of secotaxanes, small changes to a natural pharmacophore may be an attractive avenue to generate compounds capable of inhibiting the noxious βIIItubulin function. 6. Conclusion βIII-Tubulin is the most investigated tubulin isotype. Its roles in neural development and oncology have warranted this intensive study. Recent analysis has demonstrated that βIII-tubulin is part of a complex, pro-survival, molecular pathway activated by hypoxia and poor nutrient supply. Induction of this pathway in cancer is associated with an aggressive phenotype in the majority of patients, with some exceptions. In this sense, βIII-tubulin is a pure prognostic biomarker whenever its association is linked to a more complex phenotype. On the other hand, βIII-tubulin is not a predictive biomarker of taxaneresistance as originally thought, as its role in determining biological aggressiveness require other factors. Complete elucidation of βIII-tubulin interactions, both upstream and downstream, may facilitate development of novel anti-cancer agents and ultimately transition βIII-tubulin from a pure prognostic to an actionable predictive biomarker. Acknowledgments We are grateful to Sandra Lobo for her advice and valuable administrative support. This study was supported by a Connecticut State Grant (DPH# 2014-0132, CF) and by a liberal donation from Rudy and Sally Ruggles. This work is dedicated to Monica DeFeo who lost her courageous battle against cancer at the young age of 53. Sponsors of the study did not have any role in the manuscript conception. References Akasaka, K., Maesawa, C., Shibazaki, M., Maeda, F., Takahashi, K., Akasaka, T., Masuda, T., 2009. Loss of class III beta-tubulin induced by histone deacetylation is associated with chemosensitivity to paclitaxel in malignant melanoma cells. J. Invest. Dermatol. 129 (6), 1516–1526. Andre, N., Braguer, D., Brasseur, G., Goncalves, A., Lemesle-Meunier, D., Guise, S., Jordan, M.A., Briand, C., 2000. Paclitaxel induces release of cytochrome c from mitochondria isolated from human neuroblastoma cells'. Cancer Res. 60 (19), 5349–5353. Andreoli, M., Persico, M., Kumar, A., Orteca, N., Kumar, V., Pepe, A., Mahalingam, S., Alegria, A.E., Petrella, L., Sevciunaite, L., et al., 2014. Identification of the first inhibitor of the GBP1:PIM1 interaction. Implications for the development of a new class of anticancer agents against paclitaxel resistant cancer cells. J. Med. Chem. 57 (19), 7916–7932. Aoki, D., Oda, Y., Hattori, S., Taguchi, K., Ohishi, Y., Basaki, Y., Oie, S., Suzuki, N., Kono, S., Tsuneyoshi, M., et al., 2009. Overexpression of class III beta-tubulin predicts good response to taxane-based chemotherapy in ovarian clear cell adenocarcinoma. Clin. Cancer Res. 15 (4), 1473–1480. Azuma, K., Sasada, T., Kawahara, A., Takamori, S., Hattori, S., Ikeda, J., Itoh, K., Yamada, A., Kage, M., Kuwano, M., et al., 2009. Expression of ERCC1 and class III beta-tubulin in non-small cell lung cancer patients treated with carboplatin and paclitaxel. Lung Cancer 64 (3), 326–333. Barford, D., 2004. The role of cysteine residues as redox-sensitive regulatory switches. Curr. Opin. Struct. Biol. 14 (6), 679–686. Caccamo, D., Katsetos, C.D., Herman, M.M., Frankfurter, A., Collins, V.P., Rubinstein, L.J., 1989. Immunohistochemistry of a spontaneous murine ovarian teratoma with neuroepithelial differentiation. Neuron-associated beta-tubulin as a marker for primitive neuroepithelium. Lab. Investig. 60 (3), 390–398. Cai, P., Lu, P., Sharom, F.J., Fang, W.S., 2013. A semisynthetic taxane Yg-3-46a effectively evades P-glycoprotein and beta-III tubulin mediated tumor drug resistance in vitro. Cancer Lett. 341 (2), 214–223. Caracciolo, V., D'Agostino, L., Draberova, E., Sladkova, V., Crozier-Fitzgerald, C., Agamanolis, D.P., de Chadarevian, J.P., Legido, A., Giordano, A., Draber, P., et al., 2010. Differential expression and cellular distribution of gamma-tubulin and betaIII-tubulin in medulloblastomas and human medulloblastoma cell lines. J. Cell. Physiol. 223 (2), 519–529. Carrara, L., Guzzo, F., Roque, D.M., Bellone, S., Emiliano, C., Sartori, E., Pecorelli, S., Schwartz, P.E., Rutherford, T.J., Santin, A.D., 2012. Differential in vitro sensitivity to patupilone versus paclitaxel in uterine and ovarian carcinosarcoma cell lines is linked to tubulin-beta-III expression. Gynecol. Oncol. 125 (1), 231–236. Cicchillitti, L., Penci, R., Di Michele, M., Filippetti, F., Rotilio, D., Donati, M.B., Scambia, G., Ferlini, C., 2008. Proteomic characterization of cytoskeletal and mitochondrial class III beta-tubulin. Mol. Cancer Ther. 7 (7), 2070–2079. Colombo, N., Kutarska, E., Dimopoulos, M., Bae, D.S., Rzepka-Gorska, I., Bidzinski, M., Scambia, G., Engelholm, S.A., Joly, F., Weber, D., et al., 2012. Randomized, open-
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Wiki review
Class III β-tubulin in normal and cancer tissues Marisa Mariani, Roshan Karki, Manuela Spennato, Deep Pandya, Shiquan He, Mirko Andreoli, Paul Fiedler, Cristiano Ferlini ⁎ Danbury Hospital Research Institute, Danbury, CT, USA
a r t i c l e
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Article history: Received 3 December 2014 Received in revised form 26 March 2015 Accepted 27 March 2015 Available online 1 April 2015 Keywords: βIII-Tubulin TUBB3 Biomarker Neural differentiation Cancer
a b s t r a c t Microtubules are polymeric structures composed of tubulin subunits. Each subunit consists of a heterodimer of α- and β-tubulin. At least seven β-tubulin isotypes, or classes, have been identified in human cells, and constitutive isotype expression appears to be tissue specific. Class III β-tubulin (βIII-tubulin) expression is normally confined to testes and tissues derived from neural cristae. However, its expression can be induced in other tissues, both normal and neoplastic, subjected to a toxic microenvironment characterized by hypoxia and poor nutrient supply. In this review, we will summarize the mechanisms underlying βIII-tubulin constitutive and induced expression. We will also illustrate its capacity to serve as a biomarker of neural commitment in normal tissues and as a pure prognostic biomarker in cancer patients. © 2015 Elsevier B.V. All rights reserved.
1. βIII-Tubulin and the microtubules Microtubules are filamentous, cytoskeletal polymers found in all eukaryotes and are involved in critical cellular processes such as mitosis, cell motility, and intracellular transport. The core cylinders of microtubules are composed of basic building blocks, α- and β-tubulin monomers, that spontaneously assemble to form functional subunits called heterodimers. These α/β heterodimers polymerize in a linear fashion to form “head to tail” polar protofilaments with β-tubulin facing headwards and α-tubulin oriented toward the tails. Along with the head to tail interaction, heterodimers interact also laterally to form the cylinder that is the microtubule. Although the term “cytoskeletal” may imply stasis and permanence, microtubules are in fact highly dynamic and ethereal. The vibrant kinetics of microtubule assembly and disassembly are self-regulated at least in part by β-tubulins, which are not only structural proteins but GTPases as well. As critical yet ever-changing components of cell function, microtubules are often targeted when designing novel therapeutics and pharmaceuticals (Jordan and Kamath, 2007). Multiple genes encode α- and β-tubulin isotypes. These genes show high homology (Ferlini et al., 2007) and conservation across vertebrate species (Tuszynski et al., 2006) indicating origins from a common Abbreviations: βIII-Tubulin, class III β-tubulin; MAP, microtubule associated proteins; ABC, ATP binding cassette; UTR, untranslated region; CFEOM3, congenital fibrosis of extraocular muscles 3; GBP-1, guanylate-binding protein 1; PIM-1, proviral integration site 1; HIF-1α, hypoxia inducible factor 1α; HIF-2α, hypoxia inducible factor 2α. ⁎ Corresponding author at: Danbury Hospital Research Institute, 131 West Street, Danbury, CT, USA. E-mail address: [email protected] (C. Ferlini).
http://dx.doi.org/10.1016/j.gene.2015.03.061 0378-1119/© 2015 Elsevier B.V. All rights reserved.
ancestral gene. Both α- and β-tubulin isotypes, like cytokeratin isotypes, demonstrate differential tissue expression patterns during embryogenesis, suggesting diversity in functionality and a specific role in the differentiation processes (Sullivan and Cleveland, 1986). At least seven β-tubulin isotypes have been identified in the human genome (Ferlini et al., 2007). These vary in the final 15 C-terminus residues which are exposed for the interaction with microtubule associated proteins (MAPs). They also differ in the composition of the 3′-UTR flanking region implicated in transcriptional and translational regulation. These modifications confer properties which match the metabolic and structural needs of a given tissue. βIII-Tubulin is encoded by the TUBB3 gene which firstly appeared in fish, both osteoichthyes and chondrichthyes (Tuszynski et al., 2006; Joe et al., 2008), thus coinciding with the time of vertebrate evolution and exposure to the higher tension of oxygen (Towe, 1970). βIII-Tubulin is constitutively expressed in the central and peripheral nervous systems and in the testes, specifically in Sertoli cells. In in vitro cultured cancer cells, constitutive TUBB3 expression seems regulated in a cell-cycle dependent way, with maximal expression at the G2/M phase of the cell cycle (Shibazaki et al., 2012). Such constitutive expression is linked to the expression levels of the RE1-silencing transcription factor (REST). REST binds to the first TUBB3 exon and suppresses the constitutive TUBB3 expression (Gao et al., 2012). In other tissues, both normal and neoplastic, the expression of βIIItubulin is induced by exposure to a toxic microenvironment featured by hypoxia and poor nutrient supply. In this review, we will describe the regulation of TUBB3 in humans and its functional role in normal and diseased tissues. We will also
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Fig. 1. Representative multiplexed fluorescent immunohistochemistry of a high grade serous ovarian cancer case stained with anti-TUBB3. In blue — cell nuclei stained with DAPI; in green — stromal cells stained with anti-vimentin; in yellow — epithelial cancer cells stained with anti-cytokeratin; in pink — TUBB3 expression stained with anti-TUBB3 (clone TUJ1). The TUJ1 pattern of staining is cytoplasmic and as in this case is often heterogeneous within the cancer cell population in high grade serous ovarian.
provide a context for understanding why βIII-tubulin has been extensively documented as a biomarker of poor outcome in a panel of solid malignancies. 2. Gene structure of human TUBB3 The human TUBB3 gene is located on chromosome 16q24.3 and consists of 4 exons that transcribe a protein of 450 aa. A shorter isoform of 378 aa derived from the alternative splicing of exon 1 is devoid of a part of the N-terminus and may be responsible for mitochondrial expression (Andre et al., 2000; Cicchillitti et al., 2008), whose functional significance remains unknown. Similar to other β-tubulin isotypes, βIII-tubulin has a GTPase domain which is essential in regulating microtubule dynamics (Katsetos and Draber, 2012). Class I (the most represented and constitutively expressed isotype) and βIII-tubulin differ by just 13 aa within the 1–429 aa region, whereas region 430–450 aa is completely divergent. These variations in the primary structure affect the paclitaxel binding domain (Ferlini et al., 2005, 2007; Magnani et al., 2006) on βIII-tubulin and may account for the ability of this isotype to confer resistance to paclitaxel initiated apoptosis (Ferlini et al., 2009). Since paclitaxel is a Nur-77 mimic, βIII-tubulin may represent the inherent survival pathway to Nur-77 induced cell death (Ferlini et al., 2009). In fact, Nur-77 translocation from the nucleus to mitochondria activates a cell death program (Lin et al., 2004), which is inhibited by βIII-tubulin expression (Ferlini et al., 2009). 3. Expression and function of βIII-tubulin A recent PUBMED search using keywords “class III β-tubulin” or “TUBB3” retrieved 610 references. Of these, 51% (309/610) relate to its role in neural differentiation. The knowledge of TUBB3 as a neuronal marker dates back to 1989 when the first monoclonal anti-class III βtubulin antibody (TUJ1) became available (Caccamo et al., 1989). The expression of βIII-tubulin by medulloepithelial rosettes suggested that this isotype was one of the earliest markers to signal neuronal commitment in primitive human neuroepithelium. This hypothesis was later confirmed in other species (Lee et al., 1990; Linhartova et al., 1992). The critical importance of the TUBB3 gene in neural development has also been confirmed by the study of TUBB3 mutations in congenital syndromes. A panel of at least eight heterozygous missense mutations was shown to produce congenital fibrosis of extraocular muscles 3 (CFEOM3), a group of eye movement disorders caused by the dysfunction of the oculomotor nerve (Tischfield et al., 2010). The classical CFEOM3 symptoms, ptosis and restricted eye movements, are observed
at birth. These symptoms are associated with additional nervous system disorders. CFEOM3 patients exhibit peripheral axonal neuropathy, facial paralysis, and often intellectual and behavioral impairments. Conventional neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerves along with dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. The commonest TUBB3 mutation causing CFEOM3 results in a R262C amino acid substitution. A TUBB3R262C knock-in mouse model reveals axon guidance defects of the oculomotor nerve and central axon tracts without evidence of cortical cell migration abnormalities (Tischfield et al., 2010). By contrast, six other diverse missense mutations in the TUBB3 gene were observed in patients with cortical disorganization and axonal abnormalities associated with pontocerebellar hypoplasia but without ocular motility defects typical of CFEOM3 (Poirier et al., 2010). The diverse spectra of phenotypic changes related to congenital TUBB3 mutations highlights the pivotal role this protein plays in neuronal development. As further evidence of its specificity, TUBB3 inactivation impairs neural progenitor proliferation which cannot be rescued or restored by other β-tubulins (Saillour et al., 2014). TUBB3 expression is also constitutively expressed in the testis where it is regulated by androgen exposure during ontogenesis in mouse and rat Sertoli cells (De Gendt et al., 2011). Hormonal influence of TUBB3 expression has also been identified in neoplasia. Breast carcinoma cells, for example, show TUBB3 under the control of estradiol via the estrogen receptor (Saussede-Aim et al., 2009). In prostate cancer, βIIItubulin expression is strongly associated with both TMPRSS2:ERG rearrangement, ERG expression and PTEN deletions, three key oncogenetic features of aggressive prostate cancer (Tsourlakis et al., 2014). Also, colorectal cancer is more aggressive in young male patients in whom testosterone elevation and activation of TUBB3 are connected with poor outcome (Shahabi et al., 2013; Orsted et al., 2014). 4. βIII-Tubulin and taxane-resistance: a need for critical revision? The primary interest in βIII-tubulin in oncology relates to its putative role in taxane-resistance. Large metanalyses (Reiman et al., 2012) and a number of additional smaller studies (Ferrandina et al., 2007; Urano et al., 2006; Ohishi et al., 2007; Umezu et al., 2008; Terry et al., 2009; Ishida et al., 2009; Hayashi et al., 2009; Azuma et al., 2009; Yoon et al., 2010; Ploussard et al., 2010; Miyamoto et al., 2010; Koh et al., 2010; Mariani et al., 2012; Leskela et al., 2011; Hirai et al., 2011; Levallet et al., 2012; Zhang et al., 2012; Vilmar et al., 2012; Roque et al., 2014) have clearly indicated that βIII-tubulin is linked to poor outcome (See Fig. 1.). Taxanes inhibit tubulin depolymerization thereby increasing
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intracellular levels of polymerized tubulin and arresting cellular functions. Early pivotal in vitro studies demonstrated that different proportions of tubulin isotypes affect microtubule dynamics. In particular, βIII-tubulin was shown to enhance the rate of tubulin depolymerization (Panda et al., 1994), a feature that could account for resistance to taxanes, drugs that promote tubulin assembly. Indeed, a number of early studies of ovarian (Kavallaris et al., 1997; Mozzetti et al., 2005) and lung (Seve et al., 2005) carcinomas supported this notion. However, this direct correlation was challenged by subsequent findings. For example, when βIII-tubulin was moderately expressed under a conditional promoter, there was only a weak induction (less than twofold) of paclitaxelresistance (Hari et al., 2003). Furthermore, increased expression of βIIItubulin was documented in patients treated with drugs acting as direct inhibitors of tubulin polymerization such as Vinca alkaloids (Seve et al., 2007). Even more problematic, in breast cancer (Galmarini et al., 2008; Wang et al., 2013), clear cell ovarian carcinoma (Aoki et al., 2009) and melanoma (Akasaka et al., 2009), studies have reported that high expression of βIII-tubulin was linked to sensitivity to taxane-based chemotherapy and not resistance. In this sense, in tissues where constitutive βIII-tubulin is present, low expression of this tubulin isotype is a sign of de-differentiation and more aggressive disease. As an apparent paradox, in tissues where constitutive βIII-tubulin is absent, its aberrant expression is associated in most cases, but not always, with an aggressive phenotype regardless if the disease is treated with a taxane or not (Katsetos and Draber, 2012; Akasaka et al., 2009; Katsetos et al., 2003a,b; Caracciolo et al., 2010; Katsetos et al., 2011; Karki et al., 2013). Postulating that βIII-tubulin alone regulates microtubule dynamics and induces resistance to taxanes is clearly an over-simplification. In fact, many factors are capable of binding to βIII-tubulin, such as γtubulin (Katsetos et al., 2007, 2009), SEMA6A (Prislei et al., 2008), GBP-1 (De Donato et al., 2012) and Erp57 (Cicchillitti et al., 2008). Moreover, TUBB3 expression can occur in concert with other elements, when transcription is activated by exposure to a toxic microenvironment featured by low oxygen (Raspaglio et al., 2008, 2014) and poor nutrient supply (Raspaglio et al., 2010). In the 3′ flanking region of TUBB3, there is an E-box (5′-RCGTG-3) which binds hypoxia induced transcription factors, HIF-1α and -2α. Accordingly, βIII-tubulin staining appears in hypoxic areas within tumors (Katsetos et al., 2001). Hypoxia triggers pro-survival pathways (Raspaglio et al., 2003; McCarroll et al., 2015) rendering cells resistant to taxanes along with a number of other drugs. In this context, βIII-tubulin is not a passive bystander. In cell lines with an aggressive phenotype and constitutive βIII-tubulin expression, βIII-tubulin knockdown is associated with reduced growth and increased chemotherapy sensitivity when compared with control clones (Gan et al., 2007; McCarroll et al., 2010). β-tubulins are redoxcontrolled proteins. As such, they have cysteine residues that can be reversibly oxidized resulting in the modification of protein function (Barford, 2004). Khan and Luduena have proposed that oxidative stress and the thioredoxin system regulate the dimer/microtubule equilibrium (Khan and Luduena, 1991). Proteomic analysis has revealed that many factors that bind to βIII-tubulin are involved in the oxidative stress and glucose deprivation response (Cicchillitti et al., 2008). In structural terms, constitutive Class I (TUBB) and Class IVb (TUBB2C) β-tubulins contain a cysteine at position 239, while βIII-tubulin has a cysteine at position 124. Position 239 can be readily oxidized while position 124 is relatively resistant to oxidation (Joe et al., 2008). Thus, a relative abundance of βIII-tubulin in situations of oxidative stress should enhance pro-survival signals and cell integrity (De Donato et al., 2012). This concept appears especially plausible in light of the fact that, as mentioned above, βIII-tubulin first appears in evolutionary history at the time of increased exposure to oxygen. Among the components of the cytoskeletal gateway to resistance, a leading role is played by the GBP-1 (guanylate-binding protein 1) GTPase. This enzyme directly binds to βIII-tubulin and facilitates the incorporation of a panel of pro-survival factors into the cytoskeleton including PIM-1 (Proviral Integration Site 1) and another 19 kinases (De Donato et al.,
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2012). Integrated analysis of GBP-1 along with upstream βIII-tubulin regulators (HIF-1α and -2α, miR-200c) and downstream effectors of βIII-tubulin enables accurate identification of a subset of cancer patients in whom the aggressive pathway is activated (De Donato et al., 2012; Raspaglio et al., 2014; Prislei et al., 2013). In functional terms, the expression of βIII-tubulin in normal tissues seems to be finalized to the protection of the most precious progenitors in tissues. This phenomenon seems not specific of the neural progenitors (Draberova et al., 2008; Petschnik et al., 2011; Foudah et al., 2014). In this sense, βIII-tubulin could be considered as a marker of stemness. Also within cancer tissues, βIII-tubulin expression may simply indicate an enrichment of cancer stem-like cells (Moitra et al., 2011; Li et al., 2014), featured by certain ABC transporters such as ABCB1 (known as Pgp/MDR1), ABCG2 (known as BCRP) and very efficient systems of DNA repair. The coordinate expression of multiple factors aimed at the stem cell protection from xenobiotics may then cause the multidrug resistance phenotype responsible for poor response to chemotherapy in patients. In summary, βIII-tubulin is not a predictive biomarker of taxaneresistance. Instead, βIII-tubulin is a pure prognostic biomarker only when its expression is conditioned by a toxic microenvironment. However, when its expression is driven by other factors, the βIIItubulin role is neutral or even opposite, acting as a marker of a more differentiated and less aggressive disease. 5. βIII-Tubulin as a drug target Since the discovery of βIII-tubulin's role in drug-resistance, a number of strategies have been pursued to inhibit its function. An early approach consisted of high throughput screening of cells over-expressing βIIItubulin with novel anti-tubulin agents. This strategy led to the synthesis of IDN5390 (Ferlini et al., 2005) and other seco-taxanes (Pepe et al., 2009). These drugs were designed in silico through computational modeling of the paclitaxel binding domain of βIII-tubulin, which is slightly different from that of class I, the most expressed β-tubulin isotype. For the fact that βIII-tubulin and the ABCB1 efflux pump are co-expressed in the same cancer stem-like cells, it is not surprising that drugs particularly active against βIII-tubulin are not a substrate of ABCB1 and produce cytotoxic effects in multidrug resistant cell lines (Ferlini et al., 2005; Pepe et al., 2009; Cai et al., 2013; Mozzetti et al., 2008). In silico modeling provided additional insights into the potential mechanisms of βIII-tubulin inhibition. Through this analysis, epothilones, particularly, patupilone (Epothilone-B), were proposed as promising agents, a promise that was borne out when patupilone-resistant ovarian and endometrial cancer cells exhibited significant down-regulation of TUBB3 (Mozzetti et al., 2008; Carrara et al., 2012). Although patupilone is known to produce a dramatic therapeutic response in a subset of patients (Ferrandina et al., 2012), a large multicenter ovarian cancer study of this agent failed to obtain its primary endpoint (Colombo et al., 2012). We suggest that the lack of inclusion of βIII-tubulin expression as a criterion of enrollment contributed to this failure. The ex-novo creation of novel βIII-tubulin inhibitors is hampered by the absence of a simple, reliable in vitro test of βIII-tubulin function. To be active, βIII-tubulin requires dimerization, assembly in polymeric structures with additional cytoskeletal elements including MAP, and other post-translational changes which cannot be readily reproduced in vitro. An alternative strategy leverages the knowledge that βIIItubulin function is mediated through GBP-1. Unlike βIII-tubulin, GBP-1 can be expressed in vitro in an active form and its downstream interactions with prosurvival kinases such as PIM-1 (De Donato et al., 2012; Persico et al., 2015) can be quantified in response to various compounds of interest. This approach led to the identification of aza-podophyllotoxin as a potential therapeutic inhibitor of βIII-tubulin prosurvival function (Andreoli et al., 2014). Noteworthy, podophyllotoxin is a known inhibitor of tubulin polymerization and a competitive antagonist of the colchicine binding site (Loike and
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Horwitz, 1976; Cortese et al., 1977). As demonstrated by the case of secotaxanes, small changes to a natural pharmacophore may be an attractive avenue to generate compounds capable of inhibiting the noxious βIIItubulin function. 6. Conclusion βIII-Tubulin is the most investigated tubulin isotype. Its roles in neural development and oncology have warranted this intensive study. Recent analysis has demonstrated that βIII-tubulin is part of a complex, pro-survival, molecular pathway activated by hypoxia and poor nutrient supply. Induction of this pathway in cancer is associated with an aggressive phenotype in the majority of patients, with some exceptions. In this sense, βIII-tubulin is a pure prognostic biomarker whenever its association is linked to a more complex phenotype. On the other hand, βIII-tubulin is not a predictive biomarker of taxaneresistance as originally thought, as its role in determining biological aggressiveness require other factors. Complete elucidation of βIII-tubulin interactions, both upstream and downstream, may facilitate development of novel anti-cancer agents and ultimately transition βIII-tubulin from a pure prognostic to an actionable predictive biomarker. Acknowledgments We are grateful to Sandra Lobo for her advice and valuable administrative support. This study was supported by a Connecticut State Grant (DPH# 2014-0132, CF) and by a liberal donation from Rudy and Sally Ruggles. This work is dedicated to Monica DeFeo who lost her courageous battle against cancer at the young age of 53. Sponsors of the study did not have any role in the manuscript conception. References Akasaka, K., Maesawa, C., Shibazaki, M., Maeda, F., Takahashi, K., Akasaka, T., Masuda, T., 2009. Loss of class III beta-tubulin induced by histone deacetylation is associated with chemosensitivity to paclitaxel in malignant melanoma cells. J. Invest. Dermatol. 129 (6), 1516–1526. Andre, N., Braguer, D., Brasseur, G., Goncalves, A., Lemesle-Meunier, D., Guise, S., Jordan, M.A., Briand, C., 2000. Paclitaxel induces release of cytochrome c from mitochondria isolated from human neuroblastoma cells'. Cancer Res. 60 (19), 5349–5353. Andreoli, M., Persico, M., Kumar, A., Orteca, N., Kumar, V., Pepe, A., Mahalingam, S., Alegria, A.E., Petrella, L., Sevciunaite, L., et al., 2014. Identification of the first inhibitor of the GBP1:PIM1 interaction. Implications for the development of a new class of anticancer agents against paclitaxel resistant cancer cells. J. Med. Chem. 57 (19), 7916–7932. Aoki, D., Oda, Y., Hattori, S., Taguchi, K., Ohishi, Y., Basaki, Y., Oie, S., Suzuki, N., Kono, S., Tsuneyoshi, M., et al., 2009. Overexpression of class III beta-tubulin predicts good response to taxane-based chemotherapy in ovarian clear cell adenocarcinoma. Clin. Cancer Res. 15 (4), 1473–1480. Azuma, K., Sasada, T., Kawahara, A., Takamori, S., Hattori, S., Ikeda, J., Itoh, K., Yamada, A., Kage, M., Kuwano, M., et al., 2009. Expression of ERCC1 and class III beta-tubulin in non-small cell lung cancer patients treated with carboplatin and paclitaxel. Lung Cancer 64 (3), 326–333. Barford, D., 2004. The role of cysteine residues as redox-sensitive regulatory switches. Curr. Opin. Struct. Biol. 14 (6), 679–686. Caccamo, D., Katsetos, C.D., Herman, M.M., Frankfurter, A., Collins, V.P., Rubinstein, L.J., 1989. Immunohistochemistry of a spontaneous murine ovarian teratoma with neuroepithelial differentiation. Neuron-associated beta-tubulin as a marker for primitive neuroepithelium. Lab. Investig. 60 (3), 390–398. Cai, P., Lu, P., Sharom, F.J., Fang, W.S., 2013. A semisynthetic taxane Yg-3-46a effectively evades P-glycoprotein and beta-III tubulin mediated tumor drug resistance in vitro. Cancer Lett. 341 (2), 214–223. Caracciolo, V., D'Agostino, L., Draberova, E., Sladkova, V., Crozier-Fitzgerald, C., Agamanolis, D.P., de Chadarevian, J.P., Legido, A., Giordano, A., Draber, P., et al., 2010. Differential expression and cellular distribution of gamma-tubulin and betaIII-tubulin in medulloblastomas and human medulloblastoma cell lines. J. Cell. Physiol. 223 (2), 519–529. Carrara, L., Guzzo, F., Roque, D.M., Bellone, S., Emiliano, C., Sartori, E., Pecorelli, S., Schwartz, P.E., Rutherford, T.J., Santin, A.D., 2012. Differential in vitro sensitivity to patupilone versus paclitaxel in uterine and ovarian carcinosarcoma cell lines is linked to tubulin-beta-III expression. Gynecol. Oncol. 125 (1), 231–236. Cicchillitti, L., Penci, R., Di Michele, M., Filippetti, F., Rotilio, D., Donati, M.B., Scambia, G., Ferlini, C., 2008. Proteomic characterization of cytoskeletal and mitochondrial class III beta-tubulin. Mol. Cancer Ther. 7 (7), 2070–2079. Colombo, N., Kutarska, E., Dimopoulos, M., Bae, D.S., Rzepka-Gorska, I., Bidzinski, M., Scambia, G., Engelholm, S.A., Joly, F., Weber, D., et al., 2012. Randomized, open-
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