TCTP as therapeutic target in cancers

Cancer Treatment Reviews 40 (2014) 760–769

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Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv

Laboratory-Clinic Interface

TCTP as therapeutic target in cancers Julie Acunzo a,b,c,d, Virginie Baylot a,b,c,d, Alan So e, Palma Rocchi a,b,c,d,⇑ a

Inserm, U1068, CRCM, Marseille F-13009, France Institut Paoli-Calmettes, Marseille F-13009, France c Aix-Marseille Univ., Marseille F-13284, France d CNRS, UMR7258, Marseille F-13009, France e University of British Columbia, The Vancouver Prostate Centre 2660- Oak St Vancouver, BC V6H3Z6, Canada b

a r t i c l e

i n f o

Article history: Received 28 October 2013 Received in revised form 19 February 2014 Accepted 21 February 2014

Keywords: TCTP Therapeutic target Cancer Inhibitory strategy

a b s t r a c t The translationally controlled tumor protein (TCTP) is a highly conserved protein present in eukaryotic organisms. This protein, located both in the cytoplasmic and the nucleus, is expressed in various tissues and is regulated in response to a wide range of extracellular stimuli. TCTP interacts with itself and other protein including MCL1 and p53. TCTP has been shown to play an important role in physiological events, such as cell proliferation, cell death and immune responses but also in stress response and tumor reversion. Moreover, TCTP expression is associated with malignancy and chemoresistance. In this review, we will evaluate pathways regulated by TCTP and current inhibitory strategy to target TCTP in cancerous diseases. Ó 2014 Elsevier Ltd. All rights reserved.

Introduction TCTP is a highly conserved protein initially discovered in mouse tumor cells by groups interested in translational regulated genes [1]. Translationally Controlled Tumor Protein, also called histamine releasing factor (HRF), tumor protein translationally controlled 1 (Tpt1), p23 or fortilin, is over-expressed in various malignancies. Previous studies revealed that TCTP expressed both extra- and intra-cellularly is implicated in many biological processes, including development, cell growth, cytoskeleton, protein synthesis, immune response, tumor reversion, malignant transformation, and induction of pluripotent stem cells or apoptosis. A recent study of the structure from fission yeast orthologous classified TCTP under a family of small chaperone proteins. There is growing evidence in the literature that TCTP is a multifunctional protein and exerts its biological activity at the extra- and intra-cellular levels to promote growth. This protein is present in a multitude of tissues [2] but with preferential expression in mitotically active tissues. The expression of TCTP is highly regulated both at transcriptional and translational levels in addition to a wide range of extracellular signals. TCTP is also a histamine release factor when it localizes in the extra-cellular

⇑ Corresponding author. Address: Centre de Recherche en Cancérologie de Marseille, UMR1068 Inserm, Institut Paoli-Calmette, Aix-Marseille Univ, CNRS, UMR7258, 27 Boulevard Leï Roure BP30059, 13273 Marseille Cedex 9, France. Tel.: +33 626 941 287; fax: +33 491 826 083. E-mail address: [email protected] (P. Rocchi). http://dx.doi.org/10.1016/j.ctrv.2014.02.007 0305-7372/Ó 2014 Elsevier Ltd. All rights reserved.

compartment as described by initially by MacDonald et al. [3]. Involvement of TCTP on tumor reversion has attracted most attention on TCTP in recent years [4–6]. Numerous studies show that TCTP level in tumor is higher than that in the corresponding normal tissues, indicating its critical role in tumorigenesis [7,8]. Therefore, TCTP is now recognized as a therapeutic target in several cancers including prostate, breast and lung cancers. In this review, we focus on TCTP biological functions and related inhibitory strategies. TCTP structure TCTP mRNA structure The human TCTP gene consists of six exons and five introns with a total length of 3819 nucleotides (Fig. 1A) [9,10]. Gene transcription results in two mRNAs of 843 and 1163 nucleotides differing in the length of the 30 -untranslated regions generated by alternative polyadenylation. The potential impact of this 30 -terminal extension on the structure of the molecule is still unclear and the biological significance of the existence of two TCTP mRNA species is also an open question [11]. TCTP protein structure TCTP protein shows no homology with any other proteins and is a highly conserved protein identified in many eukaryotes organisms including yeast, fungus, insects, plants and mammals

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[1,3,12,13]. Thaw et al. first described the 3D structure of TCTP from Schizosaccharomyces pombe which defined, based on homologous sequences, TCTP structure for the other species [13]. The structure of TCTP protein contains three a-helices (H1, H2, H3) and nine b-sheets forming hydrophobic cores (Fig. 1B). An a-helical hairpin is formed by the two long helices H2 and H3 and protects one face of the central b-sheet. TCTP 3D structural analysis in yeast showed similarity with human protein Mss4 and its homologue in yeast, Dss4 [13]. Mss4 binds specifically to the Rab proteins (members of the Ras superfamily) and acts as a guanine nucleotide-free chaperone (GFC). The binding site between Mss4 and Rab coincides with the region of highest sequence conservation in TCTP, suggesting a potential role of TCTP as a chaperone [14]. Interestingly, the pair of helices H2–H3 of TCTP bears structural resemblance to the pair of helices H5–H6 of the apoptotic protein Bax (member of Bcl-2 family) [15]. This study demonstrated that TCTP antagonizes the function of Bax and requires its H2–H3 pair of helices to participate to the anti-apoptotic effect at the level of the mitochondria [15]. Mass spectrometry showed that Polo-like kinase 1 (PLK1) phosphorylates TCTP on two different residues, serine 46 and threonine 65 (Fig. 1C). PLK1 is a regulator of mitosis targeted for antitumor therapy [16]. TCTP phosphorylation by PLK1 is required for cell cycle progression. As Diraison et al. proposed, TCTP dephosphorylation in response to glucose stimulation may be important for its nuclear translocation [17]. In addition, Funston et al. mapped the TCTP interaction site to within residues 80–133 corresponding to the domain 2 and comprising an helix–loop–helix motif [13]. This work showed that residues within the loop contribute significantly to the interaction between TCTP and HDM2 (human homologue of MDM2). HDM2 serves as an ubiquitin ligase (E3) to target the tumor suppressor protein p53 for degradation. Nevertheless, Amson et al. have mapped an interaction interface between residues 1–68

of TCTP and HDM2 [4]. The domain 2 has been implicated in interaction between TCTP and tubulin [18], but also calcium [19], and the Na, K-ATPase alpha subunit (Fig. 1C) [20]. Furthermore, TCTP has recently been shown to interact with p53 through either domain 2 [21] or N and C-terminal regions [22]. TCTP localization and regulation TCTP localization The significance of the cellular localization of TCTP remains unclear. TCTP localizes in both the cytoplasm [23] and nucleus [24]. Arcuri’s group demonstrated that TCTP in human prostate and prostate cancer cells was mainly localized in the secretory luminal epithelial and basal layer cells. Subcellular distribution studies on prostate epithelial cells showed the presence of TCTP in the cytoplasm in interphase and its colocalization with tubulin during mitosis. Li’s group demonstrated that TCTP was present predominantly in the nucleus in HeLa cells. Recent studies reported that TCTP localized in both cytoplasm and nucleus localization differed between cell lines at the same time points [25,26]. Notably, Rid et al. [27] reported that under oxidative stress conditions TCTP translocates to the nucleus similarly to Diraison et al. findings that showed, under high-glucose conditions, a significant part of TCTP translocate in the nucleus [17]. The structural similarity between Bax and TCTP also suggests a localization of TCTP to mitochondrial membranes, which is essential for its antiapoptotic effect [15]. Moreover, TCTP can be secreted [3] and associated with tumor-suppressor-activated pathway-6 (TSAP6). TSAP6 facilitates TCTP secretion via a nonclassical pathway through exosomes which highlights the association of TCTP and TSAP6 in cytoplasm [28,29]. Interestingly, it seems that TCTP translocates into different subcellular units with cellulars growth [25]. This finding provides more evidence showing the

+1

+3499

5’UTR Intron 1

Intron 2

Intron 3

Intron 4

Intron 5

3’UTR1 +3820

+1

5’UTR Intron 1

Intron 2

Intron 3

Intron 4

Intron 5

3’UTR2

Fig. 1A. Intron–exon organization of human TCTP: five introns (black lines) and six exons (green boxes). Exon 6 comprises the 30 -UTR of the mRNA.

hydrophobic cores formed by 9 β-sheets 3 α-helices (H1, H2 and H3)

Fig. 1B. Crystal structure of human TCTP: b-sheets in green and yellow and the three a-helices in red.

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structural similaries with Mss4 interacon with Na/K-ATPase

s46

NH2 1

t65

interacon with Bcl-xL

H1

101

81

by PLK1

H2

H3

133

172

COOH

structural resemblance to H5-H6 of Bax

Tubilin and Ca2+ dinding site Fig. 1C. Global structure of human TCTP: interaction domains and homologies are indicated.

relationship between TCTP localization and function, improving the understanding of the crucial role of TCTP in tumorigenesis.

phorbolesters or lipopolysaccharides [34], cytotoxic agents like cisplatin or etoposide [24,35], heavy metals [36], Ca2+ [19], or dioxins [37] (Fig. 2A).

TCTP expression regulation Transcriptional regulation TCTP expression level is highly regulated at both transcription and translation levels. In order to predict transcription factor binding sites of TCTP, Andree et al., compared promoter regions of TCTP in human, mouse, rat, rabbit, and dog [30]. This study reported that the promoter regions of TCTP are highly conserved among these species. Furthermore, they report for the first time that TCTP gene expression is controlled by cAMP signaling via phosphorylation dependent activation of CRE/CREB interaction (Fig. 2A) [30]. A chromatin immunoprecipitation-based cloning strategy identified two CHD1L-binding motifs in the 5-flanking region of TCTP. Indeed, binding CHD1L (chromodomain helicase/ATPase DNA binding protein 1-like gene) to the promoter region of TCTP activates its transcription [31]. Recently, Amson et al. found a conserved p53 responsive element within the TCTP promoter region, upstream of the first ATG site (Fig. 2A) [4]. They further showed direct transcriptional repression of TCTP by p53. However, it has recently been shown that p53 positively regulates the basal expression of TCTP in colorectal carcinoma cell line HCT116. Moreover, there is a positive correlation in the expression of p53 and TCTP only in normal tissues but not in cancer cells where p53 is often mutated or non-functional [32]. TCTP expression may also be regulated by androgens in prostate cancer cells [33]. Finally, a wide variety of chemicals are able to induce the TCTP transcription, including

Translational regulation There is significant evidence to suggest that the synthesis of TCTP is regulated at the translational level [1,12,38]. The sequence of TCTP mRNA displays features typical of translationally controlled mRNAs, including a 50 -terminal oligopyrimidine tract (50 -TOP) and a 50 -UTR with a high CG-content. In 2002, Bommer et al. showed that TCTP mRNA adopts a complex secondary structure with extended base-paired areas involving about two-thirds of the molecule. Due to this extended secondary structure, TCTP mRNA is subject to negative translational regulation through the doublestranded RNA-activated-protein kinase PKR (Fig. 2B) [11,39]. PKR is known to be a dsRNA binding protein that phosphorylates, the alpha-subunit of translation factor eIF2, resulting in inhibition of protein synthesis [40,41]. The PKR-dependent regulation of TCTP levels under stress conditions (Ca2+-stress or serum starvation conditions) requires alpha-eIF2 phosphorylation [39]. As well, TCTP levels are regulated by glucose and fatty acid concentrations (palmitate) in pancreatic beta cells [17]. Protein synthesis in beta cells is highly regulated and involves activation of the PKR-like Endoplasmic Reticulum (ER) kinase (PERK) and subsequent phosphorylation of initiation factor eIF2a. In this study, they concluded that the palmitate- and glucose-dependent regulation of TCTP synthesis is mediated through a mechanism involving PERK activation and eIF2a phosphorylation.

Dioxins Heavy metals phorbolesters lipopolysaccharides Cytotoxic agents androgens cAMP Transcripon acvaon

Transcripon acvaon

Transcripon repression CREB

p53

CHD1L

p53-RE

-1027

-733

-292

-270

CRE -95

-85

tpt1 promoter Fig. 2A. Regulation of TCTP gene expression: negative regulation

CREB

CRE -54 -43 +1 tpt1 gene

, positive regulation

. Abbreviation: p53-RE: p53 responsive element.

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eIF2α

rpS6

eIF4E

TCTP: biological functions

miR-27b PKR

Cell growth and development eIF2α

+1

+3499

5’UTR TCTP mRNA Fig. 2B. Regulation of TCTP translation: negative regulation .

3’UTR1 or 3’UTR2 , positive regulation

Other mechanisms of translational regulation of TCTP have been described. The cap-binding initiation factor eIF4E is believed to preferentially activate mRNAs rich in secondary structure [42]. It has been demonstrated that the rate of TCTP synthesis is related to eIF4E activity or expression levels [43]. In addition, the multiple phosphorylation of the ribosomal protein S6 (rpS6), implicated in the translational activation of mRNAs bearing a 50 -TOP, regulates TCTP expression [44,45]. Finally, in human oral cancer cell lines, it has been shown that the human miR-27b regulates TCTP expression (Fig. 2B) [46]. Protein regulation TCTP protein regulation is not clearly understood. In 2002, Zhang et al., described an interaction between the anti-apoptotic protein Mcl-1 (Myeloid cell leukemia 1 protein) and TCTP (Fig. 2C). They further showed, by using a Mcl-1-siRNA and a Mcl-1 binding-defective mutant of TCTP, that Mcl-1 stabilizes TCTP protein without changing the amount of TCTP mRNA. Through its binding to Mcl-1, TCTP becomes more stabilized and less susceptible to degradation [47]. More recently, Rocchi et al., demonstrated that Hsp27 directly interacts with TCTP and confers its protection via the ubiquitin–proteasome pathway (UPP) (Fig. 2C) [26].

TCTP knockout in mice is lethal in utero due to inhibition of cell proliferation and consequent profound cellular apoptosis [15,48]. TCTP/ embryos suffered from reduced cell number and increased apoptosis at embryonic stage day 5.5 (E5.5) and subsequently died around E9.5–10.5 [48]. Moreover, TCTP knockdown studies in Drosophila cause lethality in late first-instar larvae and result in reduced cell size, cell number and organ size [49]. Those observations highlight the crucial role of TCTP for normal development. Hsu et al. reported that reducing Drosophila TCTP (dTCTP) levels mimic Drosophila Rheb (dRheb) (Ras homologue enriched in brain) mutant phenotypes. Rheb is a Ras superfamily GTPase, required in mTOR (mammalian Target of Rapamycin) cascade. Although they proposed that TCTP function as a growth-regulating protein by the stimulation of GDP/GTP exchange of human Rheb (hRheb), recent studies to not support these findings. Other studies show that CTP does not act as a guanine nucleotide exchange factor for Rheb [50] nor regulate mTOR signaling [51]. There appears to be a link between TCTP and mTOR pathways, but further investigation is required to elucidate the precise mechanism. Cell cycle Gachet et al. demonstrate that TCTP binds to tubulin and associates with microtubules during specific phases of the cell cycle (Fig. 3B) [18]. At metaphase, TCTP is also bound to the mitotic spindle, and is detached from the spindle during metaphase–anaphase transition. In a two hybrid screening TCTP has been identified as an interactor of the Polo-box domain of PLK1 [52]. Phosphorylation of TCTP by PLK1 is essential for cell cycle progression. PLK1 phosphorylates TCTP on two serine residues (serine 46 and 64) driving to the decrease of the microtubule-stabilizing activity of TCTP and to the

Ubiquitination

UU U

Hsp27 Cellular stress

TCTP

TCTP TCTP

TCTP

19S 20S

Proteasome

19S

Apoptosis Fig. 2C. Regulation of TCTP protein stability: Hsp27 and Mcl-1 protect TCTP to degradation and prevent apoptosis.

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increase in microtubule dynamics [52]. Latter findings identified threonine 65 as the second TCTP residue phosphorylated by PLK1 [16]. Serine 64 may also have an impact on the accessibility to phosphorylation of the adjacent residue, by inducing protein conformational changes. Cucchi et al. confirmed, by experiments of PLK1 silencing, that reduction of PLK1 in tumor cells resulted in G2/M phase cell-cycle blockage [16]. This important point may further explain on the important role of TCTP in tumorigenesis. In tumors, PLK1 is often overexpressed, and TCTP phosphorylation should thus increase leading to faster cell cycle progression. This increased cell progression may result in incomplete mitosis resulting in daughter cells that inherit incompletely replicated genomes. This may result in a plethora of mutations that may result in malignant transformation. TCTP also interacts with the checkpoint with forkhead and ring finger domain (CHFR) E3 ubiquitin ligase that binds microtubules (Fig. 3A) [53]. CHFR is a crucial checkpoint protein for cell cycle progression and tumor suppression. TCTP– CHFR interaction occurring in the mitotic spindle is stable throughout the cell cycle and is dissociated upon microtubules dissociation [53]. This study shows that CHFR, when dissociated from the spindle, is able to interact with TCTP to prevent mitotic entry. In addition, TCTP knockout in mouse was followed by a reduction of cyclin D and cyclin E suggesting that TCTP control cell proliferation via a regulation of proteins synthesized for S phase entry [48]. Interaction between TCTP, F-actin, tubulin, PLK, the translation elongation factors eEF1A and its guanine nucleotide exchange eIF1B-b confirm its involvement in cell cycle (Fig. 3A) [18,54,55]. Finally, the C-terminal domain of TCTP interacts with the third cytoplasmic domain of Na/K-ATPase, a signal transducer regulating cell growth and associated with cancer (Fig. 3A) [20]. TCTP overexpression induced inhibition of Na/K-ATPase activity, phosphorylation of EGFR (epidermal growth factor receptor), activation of Ras/Raf/Erk pathway (a downstream pathway of EGFR) and also induced phosphorylation of PI3K/Akt and PLC-c pathways (two downstream pathways of EGFR) [56].

Cell death TCTP is an antiapoptotic protein TCTP plays a key role in the regulation of apoptosis. Through its interaction with Mcl-1, TCTP regulates antiapoptotic activity by suppressing Mcl-1 degradation by blocking its ubiquitination [24,57,58]. Nevertheless, Graidist et al. reported that TCTP and Mcl-1 could independently protect cells from apoptosis [59]. TCTP could interact with others Bcl-2 family members like Bcl-xL [58] or Bax (Fig. 3B) [15]. Yang et al. identified Bcl-xL as a novel antiapoptotic TCTP-interacting protein. They mapped the interaction site to the N-terminal region of TCTP and the Bcl-2 homology domain 3 of Bcl-xL and demonstrated that TCTP N-terminal region mediates inhibition of apoptosis [58]. This finding corresponds to Zhang et al. report that shows that Arg21 in the N-terminal region of TCTP was critical for TCTP binding to Mcl-1 [47]. The dimerization of the proapoptotic protein Bax is required for its apoptotic activity. Susini et al. demonstrated that TCTP prevents the apoptotic effect of Bax by inserting into the mitochondrial membrane and inhibiting Bax dimerization but unlike Mcl-1 and Bcl-xL, TCTP does not bind Bax directly (Fig. 3B) [15]. As we previously mentioned, Amson et al., reported that TCTP directly associates with the E3 ubiquitin ligase MDM2, increasing MDM2-mediated ubiquitination of p53 and promoting its degradation [60]. Since p53 promotes apoptosis in cancer cells, TCTP also prevents apoptosis by destabilizing p53 [4,21]. Interestingly, Nutlin-3, a protein that promotes apoptosis, blocks interaction between MDM2 and TCTP. The same regulation on p53 expression has been recently found by Rocchi et al. in castration-resistant prostate cancer (CRPC). CRPC cells overexpressing TCTP loses p53 expression. Conversely, TCTP silencing using antisense oligonucleotide (ASO) of these cells restores p53 expression in vitro and in vivo. Knockdown of p53 using shRNA in TCTP-ASO treated cells restores cell viability. TCTP reduces cellular stress Recent studies proposed that TCTP has a molecular chaperone activity [13,61]. Expression of TCTP is known to be highly regulated in

Na/K-ATPase

EGFR

plasma membrane

TCTP src tubulin F-actin CHFR TCTP PLK1

Ras PLC

eIF1A

PKC

MEK

ERK

cell proliferation, cell growth, cell cycle progression Fig. 3A. Schematic representation of cell cycle regulated by TCTP and interaction with protein involved in cell proliferation and progression. Negative regulation positive regulation .

,

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Oxidative stress Heat shock Ca2+ influx

plasma membrane Bcl-xL TCTP p53

mitochondria

McL-1 Bax

MDM2

ROS caspase activation

APOPTOSIS Fig. 3B. Schematic representation of the antiapoptotic functions of TCTP and interaction with protein involved in cell death regulation. Negative regulation regulation .

response to a wide range of stress conditions, [36,37,62–64] notably heat shock [65]. Gnanasekar et al. showed that TCTP protects cells from thermal shock by potentially acting as a molecular chaperone and that TCTP overexpression protects cells from heat shock-induced cell death (Fig. 3B) [61]. Cell death can also be induced by Ca2+ influx. TCTP is a well-known calcium-binding protein [19,23,66–68] and TCTP level is controlled by the intracellular Ca2+. Graidist’s group demonstrated that TCTP is required to bind Ca2+ in order to block Ca2+-dependent apoptosis. The hypothesized is that TCTP exerts its antiapoptotic function by serving as a Ca2+ scavenger [69]. TCTP regulates oxidative stress-induced cell death Oxidative stress induced by ROS (Reactive Oxygen Species) is implicated in aging as well as in the pathophysiology of various diseases such cancer. ROS induce cell death in tissues [70] and TCTP expression has been detected in surviving cells after oxidative stress [71]. TCTP serves as antioxidant and neutralizes ROS in mammalian cells (Fig. 3B). TCTP is a critical survival factor that protects cancer cells from oxidative stress-induced cell death. DNA damage sensing and repair Recently, an important role of TCTP in response to DNA damage sensing and repair has been described [72]. Using a proteomic approach to identify differentially expressed proteins in low-dose irradiated cells, Zhang et al. found that TCTP protein level increased two fold after low-dose c radiation. They also showed that TCTP is required for the DNA-binding activity of Ku70 and Ku80 after c rays treatments, two proteins components of NHEJ (nonhomologous end-joining) mode of DSB (DNA double-strand break) repair. Thus, TCTP appears to participate in repair of DSBs. Moreover, after radiation, in the absence of TCTP, Ku70 and Ku80 levels in nuclei are reduced, likely due to disruption of their translocations into the nucleus. These results suggest TCTP has a chaperone role as previously proposed by Gnanasekar et al. in 2009. TCTP inhibition by siRNA leads to DNA damage accumulation and compromises DNA repair after radiation. TCTP appears to have a critical role in genomic stability maintenance in response and that TCTP maintain genome integrity in a p53-dependent manner.

, positive

Pluripotency and nuclear reprogramming Embryonic stem (ES) cells are pluripotent cells capable of self-renewal, unlimited proliferation, and can differentiate into any adult cell type [73]. A particular pattern of gene expression characterizes ES cells. Homeodomain transcription factor Oct4 and Nanog have been identified as master regulators of stem cell-renewal and pluripotency. Oct4 is expressed in early mammalian embryos, in ES cells [74] and occasionally in tumors [75]. Oct4 appears to regulate cell fates in a quantitative fashion and maintain a critical concentration to sustain ES cell self-renewal. Nanog is also required for maintaining the pluripotency of early post-implantation embryos and ES cells [76,77]. ES-cell-like cells can be obtained by nuclear reprogramming from somatic cells in the order to recover an embryonic-like pattern of gene expression. Many groups have attempted to better understand the process of nuclear reprogramming and to identify novel factors involved in this process. In 2007 Gurdon’s laboratory isolated novel molecules involve in transcriptional regulation of genes essential for successful nuclear reprogramming such as oct4 or nanog. This group also demonstrated that TCTP directly binds to the promoter region of oct4 and acts as a transcription factor for this gene [78]. They further showed that TCTP also indirectly activates nanog transcription or by binding to a distant site from the promoter of nanog. [78]. Thus, TCTP can induce an embryo-like pattern of gene expression and it was further shown that phosphorylated TCTP facilitates the first step of somatic cell reprogramming [79]. Another interesting point is that the role of TCTP as a transcription factor for oct4 could be directly linked to important observations that oct4 is an oncogenic factor [80]. Oct4 expression has been associated with cancer stem cells. TCTP protein was more abundant in mammary stem cells than in progeny cells [4]. Furthermore, Amson et al. explore the TCTP-p53 axis in breast cancer stem cells [4]. After TCTP inhibition in ErbB2 transgenic mouse model, they observed a 50% reduction in number of tumor mammosphere formed accompanied by increased amounts of p53 [60]. These results are preliminary, and the role of TCTP in cancer stem cell still requires further investigation.

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Immune system and inflammatory process TCTP can be secreted by an endoplasmic reticulum/Golgi-independent route and has extracellular activities. In 1995, MacDonald’s group described TCTP as a histamine release factor (HRF) that directly induced histamine release from basophils isolated from allergic donors [3,81]. Subsequent work demonstrated that TCTP induces histamine release and IL-4 and IL-13 production from IgE-sensitized basophils [82,83]. HRFs belong to a heterogeneous family of factors that stimulate histamine secretion by different mechanism. They can be divided in 2 groups: IgE-dependent and IgE-independent HRFs. HRF IgE-dependent can directly interact with IgE or not. It has been demonstrated that TCTP is an IgEdependent HRF that does not directly interact with IgE [3,84,85]. MacDonald’s group also showed that TCTP activates human eosinophils by driving eosinophils to produce IL-8 and induce an intracellular calcium response [86]. TCTP cytokine-like activity requires its dimerization via an intermolecular disulfide bond of TCTP Nterminal protein region [87,88]. Kang et al. further demonstrated that TCTP bound to B cells to induce cytokine production (IL-1 and IL-6) and identified TCTP as a B cell growth factor [89]. More recently, Yoneda K et al. reported that TCTP can stimulate bronchial epithelial cells to produce IL-8 and granulocyte–macrophage colony-stimulating factor [90]. TCTP was also shown to be expressed in thymus and is crucial for peripheral T cell maintenance and TCT-mediated cell proliferation. In summary, in addition to functioning as a histamine releasing factor, TCTP has been showed to modulate secretion of cytokines from human basophils, eosinophils, B cells, T cells and bronchial epithelial cells. Cancer cells have a many mechanisms to trick the immune system. As well, inflammation has long been associated with the development of cancer. Hence, the role of TCTP in the immune system as well as cancer development suggest that it may be an ideal target to suppress tumorigenesis that is a result of altered immune responses.

TCTP as therapeutic target for cancer TCTP and cancer Prostate cancer Prostate cancer (PC) is among the most common cancers in industrialized countries. Patients with localized disease may be treated with surgery or radiation, whereas androgen withdrawal (castration) is used as first-line therapy in patients with locally advanced and metastatic disease. While most patients initially respond well to castration, ultimately this is temporary and tumor progressed within 2 years when they become castration-resistant (CRPC). Recently, docetaxel-based regimens have demonstrated improved survival in men with CRPC in two different phase III studies. However, median overall survival was prolonged by only 2.7 months [91]. TCTP protein and mRNA is abundant in ex vivo human prostatic cancer cells, in human prostate cancer cell lines (LNCaP and PC-3) and also in the non-neoplastic human prostate epithelial cells PWR-1E. TCTP location was evident in the prostatic epithelium and weakly in the smooth muscle. TCTP is highly expression was detected into the cytoplasm of secretory luminal epithelial cells and in glandular sections. In the PWR-1E cell line, TCTP is colocalized with microtubules during mitosis [23]. In addition, TCTP protein level increased in castration-resistant cells xenografts in mice compared to castration-sensitive xenografts. Interestingly, after androgen withdrawal, TCTP expression reduces and then increases significantly when tumor progress to castration-resistance. Recently, interactions between TCTP Hsp27 has been shown that possess a crucial role in regulating the balance between cell death and

survival. Moreover, TCTP is involved in cytoprotection mediated by Hsp27, as TCTP knockdown using siRNA in LNCaP stably transfected with Hsp27, reverses the cytoprotection to androgen withdrawal and docetaxel treatments normally conferred by Hsp27 overexpression [26]. This result reveals that TCTP is an important effector of Hsp27 cytoprotective function. Furthermore, Hsp27 overexpression has been associated with multi-drug resistance in several cancers as prostate. Silencing TCTP using siRNA induced cell cycle blocking and apoptosis in PC-3 and LnCaP cell line [26,33]. A patented antisense oligonucleotide targeting against TCTP (TCTP-ASO) has been developed by Rocchi et al. This ASO inhibits cell proliferation and induces apoptosis in vitro and in vivo. Furthermore, TCTP knockdown using ASO enhances castration and docetaxel therapy. Interestingly, CRPC progression correlates with TCTP overexpression and loss of p53. TCTP knockdown restored p53 expression and function, suggesting that castrationsensitivity is directly linked to p53 expression. Combining ASOmediated TCTP knockdown with castration and/or docetaxel therapy could serve as a novel strategy to treat CRPC, with no or little toxicity for normal prostate cells. Breast cancer TCTP is weakly expressed in normal breast cells and overexpressed in breast cancer cells (BCa). Downregulation of TCTP in breast cancer cells (MCF7 and T47D) in three dimensional cultures leads to a dramatic reorganization of the malignant cell growth pattern comparable with normal growth. Deng et al., proposed for the first time TCTP as a biomarker of BCa, due to the variation in its protein expression [92]. In human breast epithelial cells, TCTP induces cell proliferation through distinct multicellular signaling pathways involving Src-dependent EGFR transactivation, ROS generation and MMP expression [93]. Telerman’s group showed in BCa cell lines that TCTP was downregulated in tumor reversion [94]. They also found, in a large cohort of individuals with BCa, that although TCTP is highly expressed in a fraction of these cancers, expression of this protein correlates with clinical and pathological parameters of aggressive disease [4]. They described TCTP as an independent predictor of poor prognosis in individuals with these tumors. The inactivation of p53 by mutations observed in some breast tumors correlates with an increase of TCTP alteration frequency, pointing the clinical relevance of TCTP/p53 regulation in BCa. This finding is consistent with study on prostate cancer that show a loss of p53 when TCTP is up-regulated. Furthermore, Amson et al. confirmed the relevance of TCTP alteration in BCa by demonstrating its involvement in BCa stem cell compartment expansion [4]. Lung cancer Among twenty screened proteins in lung cancer, TCTP was one of the most overexpressed proteins in human lung cancer cells compared to normal cells suggesting that TCTP can be a good biomarker for lung cancer [95]. In human lung carcinoma, TCTP interact with p53 protein that normally inhibits cell viability [21]. IN lung cancer, co-expression of p53 and TCTP allows a recovery of cell viability showing the cytoprotective effect of TCTP. Others cancers TCTP overexpression was also detected in human leukemia, erythroleukemias, gliomas, lymphomas, squamous cell carcinoma, colon, hepatocellular carcinoma, liver, larynx and melanoma [8]. In addition, compared to normal human tissues, TCTP has been shown to be overexpressed in colon cancer cell lines [96], and in human hepatocellular carcinoma [97]. Up-regulation of TCTP protein was also shown in other human cancer including larynx and in melanoma cell line [35,94]. In human cervical cancer cells exposed to taxol, TCTP level decreased during apoptosis [98]. Finally,

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in multiple myeloma cells (a malignant disorder of differentiated B cells) TCTP is inhibited during the reversion process and the suppression of the malignant phenotype [6,99]. Targeting TCTP Involvement of TCTP in tumorigenesis is well demonstrated and strategies to inhibit TCTP expression level are attractive. Pre-clinical studies in different cancer models using TCTP knockdown as a therapeutic strategy confirms the effect of TCTP on cell survival and show encouraging results as a potential treatment for malignancies. Antisense oligonucleotides (ASO) Down regulation of TCTP using ASO or siRNA (small interference RNA) induces cell apoptosis and cell cycle blockade and also chemosensitizes cells [26]. In vivo, TCTP ASO treatment of PC-3 xenografts significantly reduces tumor volumeand enhanced the apoptotic effect of docetaxel. As well, TCTP inhibition using ASO or siRNA induces an increase of caspase-dependant cell death in androgen-dependant cancer cell line LNCaP and inhibits cell growth and enhance chemotherapy on castration-resistant cells [26]. Interestingly, similar results have been shown using TCTP ASO in a beta insulinoma cell line, suggesting the possible use of this treatment in multiple different tumor models. siRNA or shRNA In human leukemia cancer cells, TCTP inhibition induced apoptosis in vitro and inhibited tumor progression in vivo [94]. TCTP was down regulated in tumor reversion and this inhibition using antisens in NIH3T3 cells transformed by v-src increased the proportion of revertants cells and a return to normal phenotype [6]. TCTP knockdown using shRNA in metastatic colon cancer cell line has shown inhibition of cell proliferation, cell invasion, cell migration in vitro and inhibition of tumor growth and metastasis in vivo. In these cells, inactivation of TCTP is followed by a reduced expression of ubiquitin–proteasome system like protein involved in tumor metastasis [100]. Recently, antisense mRNA of TCTP transfected into liver cancer cell line SMMC-7721 induced a decrease of cell proliferation due to cell cycle arrest and apoptosis [97]. Interestingly, in human lung carcinoma and in primary mammary tumors cells, TCTP inhibition induces p53 expression and tumoral cell apoptosis. This study clearly shows that TCTP prevents apoptosis through negative regulation of p53 [21]. Inhibitors of the histaminic pathway A novel strategy to inhibit TCTP expression is the use of antihistaminic compounds, such as hydroxyzine and promethazine, that antagonizes the histaminic receptors H1 and decreases TCTP protein expression. These compounds have shown anticancer effects by reducing cell survival in vitro and breast tumor growth in vivo [6]. These results have led to early clinical trials. TCTP inhibitors Analogues of antihistaminic drugs have been evaluated for their capacity to inhibit cell viability. Indeed, analogues including thioridazine (antipsychotic drug), sertraline (antidepressant), perphenazine (antipsychotic drug), chlorpromazine (antipsychotic drug), paroxetine (antidepressant), and flupenthixol (neuroleptic) have known to have no antihistaminic properties; however, these compound decrease cell viability of cells derived from leukemia (U937) at low concentration. In vivo, sertraline and thioridazine decreases the tumor growth in breast cancers and monocytic leukemia induced in mice, [6]. These agents appear to suppress the expression of TCTP TCTP protein [6]. More precisely, sertraline, member of selective serotonin reuptake inhibitor and thioridazine, member

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of the phenothiazine, has been shown to inhibit TCTP expression and restores p53 protein expression. Sertraline treatment promotes the binding of p53 to the p53 responsive element in the TCTP promoter [4]. Sertraline and thioridazine bind directly TCTP preventing the TSAP6-TCTP complex formation and the binding of TCTP to MDM2. Thereby, these drugs reverse the ubiquitination of p53 normally induced by TCTP [4]. Conclusion Tumorigenesis is the consequence of multiple genetic and epigenetic events that induce cell proliferation and progression of tumor growth. TCTP is implicated in a variety of cellular functions, including growth control, protein synthesis, mitosis, and apoptosis. The anti-apoptotic effect of this protein is has been clearly demonstrated and its involvement in progression of various malignancies as well as tumor reversion has been reported. Furthermore, TCTP interacts with other proteins implicated in tumorigenesis. Combined, these results suggest that TCTP is a promising target for anticancer drugs. Gene silencing technologies, including ASO, dev may represent a new therapy for targeting gene responsible of tumor progression. Conflict of interest None declared. References [1] Yenofsky R et al. Regulation of messenger-Rna utilization in mouse erythroleukemia-cells induced to differentiate by exposure to dimethylsulfoxide. Mol Cell Biol 1983;3(7):1197–203. [2] Bommer UA, Thiele BJ. The translationally controlled tumour protein (TCTP). Int J Biochem Cell Biol 2004;36(3):379–85. [3] MacDonald SM et al. Molecular identification of an IgE-dependent histaminereleasing factor. Science 1995;269(5224):688–90. [4] Amson R et al. Reciprocal repression between P53 and TCTP. Nat Med 2012;18(1):91–9. [5] Amson R et al. TPT1/TCTP-regulated pathways in phenotypic reprogramming. Trends Cell Biol 2013;23(1):37–46. [6] Tuynder M et al. Translationally controlled tumor protein is a target of tumor reversion. Proc Natl Acad Sci U S A 2004;101(43):15364–9. [7] Nagano-Ito M, Ichikawa S. Biological effects of mammalian translationally controlled tumor protein (TCTP) on cell death, proliferation, and tumorigenesis. Biochem Res Int 2012;2012:204960. [8] Miao X et al. TCTP overexpression is associated with the development and progression of glioma. Tumour Biol 2013. [9] Stapleton H, Kirkham M, Thomas G. Qualitative study of evidence based leaflets in maternity care. BMJ 2002;324(7338):639. [10] Thiele H et al. Structure of the promoter and complete sequence of the gene coding for the rabbit translationally controlled tumor protein (TCTP) P23. Eur J Biochem 1998;257(1):62–8. [11] Bommer UA et al. The mRNA of the translationally controlled tumor protein P23/TCTP is a highly structured RNA, which activates the dsRNA-dependent protein kinase PKR. RNA 2002;8(4):478–96. [12] Bohm H et al. The growth-related protein P23 of the Ehrlich ascites tumor: translational control, cloning and primary structure. Biochem Int 1989;19(2):277–86. [13] Thaw P et al. Structure of TCTP reveals unexpected relationship with guanine nucleotide-free chaperones. Nat Struct Biol 2001;8(8):701–4. [14] Lowther WT et al. The mirrored methionine sulfoxide reductases of Neisseria gonorrhoeae pilB. Nat Struct Biol 2002;9(5):348–52. [15] Susini L et al. TCTP protects from apoptotic cell death by antagonizing bax function. Cell Death Differ 2008;15(8):1211–20. [16] Cucchi U et al. Phosphorylation of TCTP as a marker for polo-like kinase-1 activity in vivo. Anticancer Res 2010;30(12):4973–85. [17] Diraison F et al. Translationally controlled tumour protein (TCTP) is a novel glucose-regulated protein that is important for survival of pancreatic beta cells. Diabetologia 2011;54(2):368–79. [18] Gachet Y et al. The growth-related, translationally controlled protein P23 has properties of a tubulin binding protein and associates transiently with microtubules during the cell cycle. J Cell Sci 1999;112(Pt 8):1257–71. [19] Kim M et al. Identification of the calcium binding sites in translationally controlled tumor protein. Arch Pharm Res 2000;23(6):633–6. [20] Jung J et al. Translationally controlled tumor protein interacts with the third cytoplasmic domain of Na, K-ATPase alpha subunit and inhibits the pump activity in HeLa cells. J Biol Chem 2004;279(48):49868–75.

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