Lessons from tumor reversion for cancer treatment : Current Opinion in Oncology

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CANCER BIOLOGY: Edited by Pierre Hainaut and Amelie Plymoth

Lessons from tumor reversion for cancer treatment

Amson, Roberta; Karp, Judith E.b; Telerman, Adama

Author Information
Current Opinion in Oncology 25(1):p 59-65, January 2013. | DOI: 10.1097/CCO.0b013e32835b7d21


Purpose of review 

Tumor reversion is the biological process by which highly tumorigenic cells lose at great extent or entirely their malignant phenotype. The purpose of our research is to understand the molecular program of tumor reversion and its clinical application. We first established biological models of reversion, which was done by deriving revertant cells from different tumors. Secondly, the molecular program that could override the malignant phenotype was assessed. Differential gene-expression profiling showed that at least 300 genes are implicated in this reversion process such as SIAH-1, PS1, TSAP6, and, most importantly, translationally controlled tumor protein (TPT1/TCTP). Decreasing TPT1/TCTP is key in reprogramming malignant cells, including cancer stem cells.

Recent findings 

Recent findings indicate that TPT1/TCTP regulates the P53–MDM2–Numb axis. Notably, TPT1/TCTP and p53 are implicated in a reciprocal negative-feedback loop. TPT1/TCTP is a highly significant prognostic factor in breast cancer. Sertraline and thioridazine interfere with this repressive feedback by targeting directly TPT1/TCTP and inhibiting its binding to MDM2, restoring wildtype p53 function. Combining sertraline with classical drugs such as Ara-C in acute myeloid leukemia may be also beneficial.


In this review, we discuss some of these reversion pathways and how this approach could open a new route to cancer treatment.


Overwhelming data have been accumulated on how normal cells become malignant. Oncogenes, tumor suppressor genes, the DNA repair machinery, microenvironment, neoangiogenesis, metabolism, chromosomal instability, immune system, and most of all, genetic evidence with thousands of mutations in the genome are just to name a few of these examples of the deregulated machinery leading to malignant transformation of normal cells [1]. Those deregulated ‘outputs’ were found to be potential targets for cancer treatment and some of them have already proven efficient in combating cancer. As of today, there is increasing evidence that more of these pharmacologic agents aimed at blocking some of the oncogenic pathways or restoring tumor suppressor function will find their way into the clinical arena. However, a major problem resides in the fact that we cannot ‘repair’ or inhibit all these abnormalities present in the cancer cell. Moreover, as anticipated, the malignant clone can become resistant to these drugs, a classical example being the development of mutations within the abl domain of the fusion bcr-abl oncogene in chronic myeloid leukemia that are associated with resistance to the tyrosine kinase inhibitor (TKI) imatinib (Gleevec). But here too, new generations of TKIs are already available that can efficiently inhibit net bcr-abl activity and overcome imatinib resistance.

A logical way to combat cancer is to understand the molecular pathways leading to reversion [2–12,13▪,14]. We hypothesized that mimicking the molecular choice made by these revertants may be one way for a tumor cell to escape from malignancy [2,3]. While the overall process of tumor reversion may not be as complicated as malignant transformation, however, the reversion program implicates hundreds of genes that are either activated or repressed in their expression [4,7,8,11,12]. At least in theory, a part of the machinery that might be spared by the transformation process could ultimately reprogram the tumor cells into revertants.

Box 1:
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As previously reviewed [2], at the beginning of the 20th century, it was found that ovarian teratocarcinoma at the early stage consists of a quite homogeneous population of cells and that during tumor progression teratocarcinomas form ‘monster tumors’ consisting of differentiated tissues such as hair or teeth. The fact that out of a cancer cell nonmalignant tissues can be formed represents a proof of principle that tumor reversion exists in human physiopathology. This is probably the best example of tumor reversion and, although very few groups continued their research in that direction, over the years, a significant amount of information was gathered to support the fact that malignant cells can quit their malignant phenotype [15–28].

In order to decipher the molecular mechanisms of tumor reversion, we generated biological models in which revertant cells were derived from cancer cells [3,5,11]. To isolate these rare revertants, we used the H1-parvovirus that kills preferentially cancer cells while sparing their normal counterparts. Infection of monoclonal cancer cells with the H1-parvovirus resulted in a massive cytopathic effect, sparing only a few cells that were not recognized as malignant anymore: the revertants [3,5,11]. Thus, we used a negative selection procedure. The differential gene-expression screening analysis between the parental cancer cells and the derived revertants showed that hundreds of genes are potentially implicated in this process [4,7,11]. Several cluster within a network of p53-regulated genes such as SIAH1, an E3-ligase and a transcriptional target of P53 [4,5,7,29]; Presenilin1, a predisposition gene for familial Alzheimer's disease [8]; TSAP6, also a transcriptional target of P53 controlling the secretion of proteins [4,30–32]; and the inhibitor of P53 activity, translationally controlled tumor protein (TPT1/TCTP) [10–12,13▪,33]. Derived from the studies on tumor reversion, these potential targets are just among the few ones that could be useful in approaching cancer treatment.


As TPT1/TCTP is the most strongly downregulated protein in the revertant cells compared with the parental cancer cells, we studied the effects of its inhibition in several biological and genetic models [2,11,12,13▪]. Decreasing the expression of TPT1/TCTP results in either apoptosis or reprogramming of cancer cells into revertants.

The antiapoptotic effect of TPT1/TCTP is documented by experiments where it stabilizes Mcl-1 [34] and Bcl-xL [35], both being antiapoptotic proteins from the bcl2 family. In this context, TPT1/TCTP inhibits the homodimerization of BAX, which is necessary to open the mitochondrial pores [10]. Mechanistically, the H2–H3 helices of TPT1/TCTP anchor into the mitochondrial membrane [10], potentiating the function of Mcl-1 and Bcl-xL. Furthermore, as recently reported, TPT1/TCTP binds to MDM2 and inhibits its autoubiquitination [13▪]. Stabilization of MDM2 has as consequence an increased proteasomal degradation of the P53 protein [13▪]. Genetic experiments have also shown that Tpt1/Tctp knockout mice are embryonically lethal [10,36], with widespread apoptosis. It is important to note here that Tpt1/Tctp heterozygous mice, which are viable, express elevated levels of P53 in their tissues [13▪]. These Tpt1/Tctp heterozygous mice are more sensitive to p53-dependent apoptosis. This haploinsufficiency to p53-dependent apoptosis is rescued when the Tpt1/Tctp heterozygous mice are crossed with p53 knockout mice, providing the genetic link between p53 and Tpt1/Tctp[13▪].

Reprogramming of malignant cells, by decreasing TPT1/TCTP levels, is illustrated by several lines of evidence [11,12,13▪]. We first used the model system developed by Bissel, consisting of three-dimensional matrigel cultures of breast cancer cells [27]. Normally, cells grow in an organized manner around a lumen and form ductal-like structures. Breast cancer cells are unable to form these organized structures and grow in clusters. When the level of TPT1/TCTP is decreased by antisense or siRNA, a striking reorganization occurs, resulting in the formation of structures reminiscent of those generated by normal breast cells [11]. As second system we used the one developed by Pollack [22] who described for the first time the phenotypic reversion of NIH3T3 cells transformed by SV40 or polyoma virus into ‘flat revertants’. When transformed by v-src, these NIH3T3 express elevated levels of Tpt1/Tctp and when transfected with antisense or siRNA-Tpt1/Tctp, they express again low Tpt1/Tctp levels, comparable to the ones found in the original untransformed NIH3T3 cells [12]. But, instead of observing the very scarce number of ‘flat revertants’, one upon a million cells by Pollack, 30% flat revertants were produced [12]. Thus, only decreasing TPT1/TCTP has as consequence overriding a robust oncogenic trigger like the one induced by v-src. In breast stem cells, whether normal or of tumor origin, TPT1/TCTP levels are elevated and its inhibition of expression by shRNA-TPT1/TCTP induces P53 protein expression with a significant decrease of the sphere forming efficiency [13▪], which represents the number of stem cells. Finally, screening of a large cohort of 508 breast cancer patients, by immunohistochemistry for the expression of TPT1/TCTP, indicates that the levels are the highest in poorly differentiated, aggressive G3 tumors [13▪]. It was further shown that TPT1/TCTP is a new independent prognostic factor for breast cancer. Patients harboring low levels of TPT1/TCTP have significantly better survival rates than those expressing high levels of TPT1/TCTP [13▪]. Altogether, these data indicate that the inhibition of intracellular TPT1/TCTP levels is sufficient to trigger either apoptosis or the tumor reversion program, providing a strong rationale that targeting TPT1/TCTP could be of therapeutic interest.


We have reported that sertraline (a widely used antidepressive drug member of the selective serotonin reuptake inhibitors, SSRIs) and thioridazine (an antipsychotic drug member of the phenothiazines) reduce the intracellular levels of TPT1/TCTP and inhibit the growth of cancer cells in vitro and in vivo[12]. Recently, we found that sertraline and thioridazine bind directly to TPT1/TCTP (Fig. 1) [13▪]. Importantly, both drugs, by binding to TPT1/TCTP, antagonize its function in the p53–MDM2 axis (Fig. 1). As mentioned above, TPT1/TCTP by stabilizing MDM2 and decreasing its autoubiquitination promotes the MDM2-dependent proteasomal degradation of P53 [13▪]. Hence, sertraline and thioridazine, by antagonizing TPT1/TCTP, restore elevated levels of WT p53 (Fig. 1), which explains how both drugs kill tumor cells. Of note, mechanistically, the binding of sertraline and thioridazine to TPT1/TCTP inhibits its binding to MDM2 [13▪]. It was recently reported that Nutlin3 also inhibits the binding of TPT1/TCTP to HDM2 providing an additional mechanistic element by which this compound operates [37▪], although through potentially different binding sites (Fig. 1). The best-known effect of Nutlin3 is to restore the WT p53 levels by antagonizing the P53–MDM2 association. In breast cancer stem cells assays, sertraline, like Nutlin3, increases the expression of P53. As P53 is a transcriptional repressor of TPT1/TCTP, sertraline will decrease the level of TPT1/TCTP and inhibit the sphere-forming efficiency in a mammosphere assay on breast cancer cells derived from ErbB2 mice [13▪]. In summary, these drugs interfere with the reciprocal repressive feedback loop between p53 and TPT1/TCTP by two different mechanisms. First, the inhibition by sertraline and thioridazine of TPT1/TCTP-dependent stabilization of MDM2 has as consequence an increase in WT p53 levels. Secondly, this increase in P53 results in a p53-dependent transcriptional repression of TPT1/TCTP. Yet another way involves a p53-independent, antiproliferative activity of sertraline that targets the mTOR signaling pathway [38], a mechanism that could relate at least in part to the proposed function of TPT1/TCTP in activating mTOR as a guanine nucleotide exchange factor (GEF) for Rheb (Fig. 1) [39]. Similarly, thioridazine exerts potent inhibition of the mTOR pathway, in line with the above-described mechanism [12,13▪,39,40]. Both sertraline and thioridazine have been rediscovered as potential anticancer drugs, by using high throughput screening technologies [41,42]. For thioridazine, the screening methodology discriminated compounds that preferentially target cancer stem cells rather than normal ones [42]. The authors suggest that thioridazine acts through a dopamine receptor-dependent mechanism; however, the relatively high concentration (10 μM) at which the drug is active indicates that this would be an off-target effect and these results should be re-evaluated taking into account the effect of thioridazine on the TPT1/TCTP–MDM2–P53 axis.

Drugs interfering with the TPT1/TCTP–MDM2–P53 axis and the γ-secretase activity. Sertraline and thioridazine bind TPT1/TCTP interfering hereby with TPT1/TCTP's inhibition of the autoubiquitination of MDM2, restoring WT p53 levels. Nutlin3 binds MDM2 and inhibits its association to p53 and to TPT1/TCTP. TPT1/TCTP has also a weak guanine nucleotide exchange factor (GEF) activity for Rheb that ultimately activates mTOR. γ-Secretase inhibitors inhibit the function of the γ-secretase complex which influences the fate of a series of substrates including APP, CD44, DCC, Notch, Jagged, Delta, E-cadherin, N-cadherin, Syndecan, ADAM 10, and ADAM 17.

As SSRIs antidepressants are used worldwide, one may wonder whether the treatment of depression with drugs targeting also TPT1/TCTP could have any effect on cancer epidemiology. Xu and colleagues [43] showed that patients treated with high doses of SSRIs have a significantly decreased risk to develop colon cancer. Only the risk for colon cancer was analyzed based on the notion that these cells have a high turnover (J. P. Collet, personal communication). More recently, independent studies confirmed this observation [44,45]. These results suggest that the activation of the tumor reversion program may not only have therapeutic applications, but also play a preventive role, eventually applicable for high-risk individuals.

There could be also other therapeutic means to decrease the TPT1/TCTP levels, in addition to using sertraline and thioridazine. TPT1/TCTP and its protein partner Hsp27 are highly overexpressed in castration-resistant prostate cancer. Hsp27 regulates TPT1/TCTP expression at the posttranslational level by protecting the latter from degradation by the proteasome [46▪]. Treatment in vivo of androgen-independent and castration-resistant tumors with TPT1/TCTP antisense oligonucleotides resulted in an inhibition of the tumor progression. Moreover, this treatment delayed also the castration-resistant tumor progression after castration in vivo[46▪].

Overexpression of miR-27b was shown to represent an effective means to inhibit the expression levels of TPT1/TCTP [47]. It was also proposed that the plasma concentrations of miR-27b could be used as a biomarker for oral cancer [47].

One may wonder whether a tumor reversion-based treatment may be an alternative to classical cytotoxic treatments or whether both approaches could be beneficial to patients. To answer this question, we performed a pilot study consisting of the ex-vivo analysis of acute myeloid leukemia (AML) patients’ cells (Fig. 2). Indeed, sertraline induces the expression of P53 and decreases TPT1/TCTP (Fig. 2a). The viability of the patients’ cells diminished significantly with the treatment of sertraline during 48 h (Fig. 2b). Importantly, the combination of 0.4 nM Ara-C with 5 μM sertraline disclosed a significant synergistic effect, indicating that the association of both types of treatments could be envisaged (Fig. 2c). A comparable synergistic effect action was also observed between thioridazine and Ara-C in AML patients [42].

Ex-vivo experiments of the effects of sertraline and Ara-C in acute myeloid leukemia (AML) patients. (a) Western blot analysis of AML patients’ cells (from patient A2 and A6) treated with sertraline or DMSO using anti-TPT1/TCTP antibodies, anti-P53 antibodies, and anti-Vinculin antibodies for equal loading. (b) Viability of ex-vivo AML cells (from patient A2 and A6) treated with 0, 1.25, 2.5, 5, and 10 μM sertraline. (c) Growth inhibition ex vivo on cells from 16 AML patients treated with either 0.4 nM Ara-C or 5 μM sertraline, or a combination of both. P = 3.0 × 10−5 was calculated with the Wilcoxon signed rank test. Additional information concerning the AML patients whose cells are tested is displayed in the online section supplementary information, https://links.lww.com/COON/A0. Growth inhibition assays and Western blot analysis were performed as described before [13▪].

A synergistic effect was also described between the downregulation of TPT1/TCTP by siRNA or antisense oligonucleotides in combination with docetaxel treatment of prostate cancer models in vitro and in vivo[46▪].


There are many more targets that could be discussed, but in the framework of this review we thought that Presenilin1 (PS1) and RECK would be of particular relevance. PS1 was identified among the genes whose expression is downregulated during the process of tumor reversion and following P53 activation [4,8]. Accordingly, we found that repression of PS1 inhibited tumor growth. PS1 encodes a predisposition gene for familial Alzheimer's disease and is a component of the γ-secretase complex (together with Nicastrin, Aph1, and Pen2), that cleaves type I receptors (Fig. 1). It is not surprising that the inhibition of PS1 influences the fate of its substrates among which APP, CD44, DCC, and Notch, modifying diverse pathways and affecting cell growth. The search for a treatment of Alzheimer's disease led to the discovery of compounds able to inhibit the γ-secretase activity (Fig. 1). Some of these γ-secretase inhibitors have an anticancer potential. Indeed, debenzazepine inhibits epithelial cell proliferation and induces differentiation of proliferative crypt cells into postmitotic goblet cells [48]. Using a murine model, with a mutant Apc tumor suppressor gene, it was also shown that debenzazepine induced goblet cell differentiation in adenomas.

A series of in-vitro and in-vivo studies have indicated that γ-secretase inhibitors have a potential anticancer activity in a wide range of tumors, including T-ALL [49,50], melanoma [51], lung cancer [52], multiple myeloma, and non-Hodgkin's lymphoma [53]. Also, the combination of γ-secretase inhibitors with other cytotoxic approaches was shown to be promising: combining the γ-secretase inhibitor (PF-03084014) with kinase inhibitors or dexamethasone may offer therapeutic advantages in T-ALL models [49]. In combination with gemcitabine, the γ-secretase inhibitor MRK003 enhances the cytopathic effect on pancreatic ductal adenocarcinoma cells and promotes widespread hypoxic necrosis [54▪]. The combination of γ-secretase inhibitors (MRK003) with trastuzumab prevents the breast tumor recurrence after trastuzumab treatment in sensitive ErbB2-positive tumors [55].

The group of Makoto Noda has identified the metalloproteinase inhibitor RECK, being a gene whose transfection into v-Ki-ras-transformed NIH3T3 cells promotes the appearance of flat revertants [56]. This group developed an original screening method based on the activation of the Reck-promoter fused to the secreted alkaline phosphatase gene [57]. This approach enabled the identification of a series of potent activators of Reck. Interestingly, disulfiram, a drug used to cure chronic alcoholism, appeared to be the most potent inducer of RECK, suppressing lung metastasis in a fibrosarcoma mouse model [57]. This strategy might represent a significant breakthrough in the identification of tumor reversion promoting drugs [14].


During these last 3 decades, there have been incredible efforts made to understand the mechanisms of cancer. We would suggest that at this point no track should be neglected in conceptualizing new drugs against cancer. Tumor reversion represents an effective means by which cancer cells are capable to reduce their malignant phenotype [2]. Unraveling the molecular pathways of tumor reversion led to the identification of key genes controlling this biological process. TPT1/TCTP [11,12] represents actually the most promising pharmacological target derived from these studies. The discovery that sertraline and thioridazine affect the fate of cancer cells by binding to TPT1/TCTP and modifying the TPT1/TCTP/MDM2/P53 equilibrium resulting in the activation of P53 expression, opens new perspectives for an alternative approach in cancer treatment [12,13▪].


A.T. and R.A. are grateful to Christian Auclair for his constant involvement and care. The authors thank all the students and postdocs in their laboratory who have been involved in this project. The authors are indebted to their colleagues, especially Pier Paolo Di Fiore, Salvatore Pece, Jean-Christophe Marine, and Moshe Oren for their support, help, and contribution.

Conflicts of interest

The authors declare no competing financial interests.

Work in the authors’ laboratories is supported by the grants from the Agence Nationale de la Recherche Programme Blanc (ANR-09-BLAN-0292-01), the European Union Network of Excellence CONTICANET, and the Association Sclérose Tubéreuse de Bourneville to A.T. and R.A.; NCI Core Grant (National Cancer Institute 2P30 CA06973-47) to J.E.K.


Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 101).


1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144:646–674.
2. Telerman A, Amson R. The molecular programme of tumour reversion: the steps beyond malignant transformation. Nat Rev Cancer 2009; 9:206–216.
3. Telerman A, Tuynder M, Dupressoir T, et al. A model for tumor suppression using H-1 parvovirus. Proc Natl Acad Sci USA 1993; 90:8702–8706.
4. Amson RB, Nemani M, Roperch JP, et al. Isolation of 10 differentially expressed cDNAs in p53-induced apoptosis: activation of the vertebrate homologue of the drosophila seven in absentia gene. Proc Natl Acad Sci USA 1996; 93:3953–3957.
5. Nemani M, Linares-Cruz G, Bruzzoni-Giovanelli H, et al. Activation of the human homologue of the Drosophila sina gene in apoptosis and tumor suppression. Proc Natl Acad Sci USA 1996; 93:9039–9042.
6. Linares-Cruz G, Bruzzoni-Giovanelli H, Alvaro V, et al. p21WAF-1 reorganizes the nucleus in tumor suppression. Proc Natl Acad Sci USA 1998; 95:1131–1135.
7. Roperch JP, Lethrone F, Prieur S, et al. SIAH-1 promotes apoptosis and tumor suppression through a network involving the regulation of protein folding, unfolding, and trafficking: identification of common effectors with p53 and p21(Waf1). Proc Natl Acad Sci USA 1999; 96:8070–8073.
8. Roperch JP, Alvaro V, Prieur S, et al. Inhibition of presenilin 1 expression is promoted by p53 and p21WAF-1 and results in apoptosis and tumor suppression. Nat Med 1998; 4:835–838.
9. Susini L, Passer BJ, Amzallag-Elbaz N, et al. Siah-1 binds and regulates the function of Numb. Proc Natl Acad Sci USA 2001; 98:15067–15072.
10. Susini L, Besse S, Duflaut D, et al. TCTP protects from apoptotic cell death by antagonizing bax function. Cell Death Differ 2008; 15:1211–1220.
11. Tuynder M, Susini L, Prieur S, et al. Biological models and genes of tumor reversion: cellular reprogramming through tpt1/TCTP and SIAH-1. Proc Natl Acad Sci USA 2002; 99:14976–14981.
12. Tuynder M, Fiucci G, Prieur S, et al. Translationally controlled tumor protein is a target of tumor reversion. Proc Natl Acad Sci USA 2004; 101:15364–15369.
13▪. Amson R, Pece S, Lespagnol A, et al. Reciprocal repression between P53 and TCTP. Nat Med 2012; 18:91–99.

Description of the reciprocal negative control between TPT1/TCTP and P53 with its clinical and pharmacological implications.

14. Telerman A, Amson R, Hendrix MJ. Tumor reversion holds promise. Oncotarget 2010; 1:233–234.
15. Braun AC. The reversal of tumor growth. Sci Am 1965; 213:75–83.
16. Braun AC. A demonstration of the recovery of the crown-gall tumor cell with the use of complex tumors of single-cell origin. Proc Natl Acad Sci USA 1959; 45:932–938.
17. Braun AC. Recovery of tumor cells from effects of the tumor-inducing principle in crown gall. Science 1951; 113:651–653.
18. Kleinsmith LJ, Pierce GB Jr. Multipotentiality of single embryonal carcinoma cells. Cancer Res 1964; 24:1544–1551.
19. Pierce GB, Dixon FJ Jr. Testicular teratomas. I. Demonstration of teratogenesis by metamorphosis of multipotential cells. Cancer 1959; 12:573–583.
20. Seilern-Aspang F, Kratochwil K. Induction and differentiation of an epithelial tumour in the newt (Triturus cristatus). J Embryol Exp Morphol 1962; 10:337–356.
21. Macpherson I. Reversion in Hamster cells transformed by Rous sarcoma virus. Science 1965; 148:1731–1733.
22. Pollack RE, Green H, Todaro GJ. Growth control in cultured cells: selection of sublines with increased sensitivity to contact inhibition and decreased tumor-producing ability. Proc Natl Acad Sci USA 1968; 60:126–133.
23. Rabinowitz Z, Sachs L. Reversion of properties in cells transformed by polyoma virus. Nature 1968; 220:1203–1206.
24. Noda M, Kitayama H, Matsuzaki T, et al. Detection of genes with a potential for suppressing the transformed phenotype associated with activated ras genes. Proc Natl Acad Sci USA 1989; 86:162–166.
25. Mintz B, Illmensee K. Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc Natl Acad Sci USA 1975; 72:3585–3589.
26. Bissell MJ, Labarge MA. Context, tissue plasticity, and cancer: are tumor stem cells also regulated by the microenvironment? Cancer Cell 2005; 7:17–23.
27. Weaver VM, Petersen OW, Wang F, et al. Reversion of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies. J Cell Biol 1997; 137:231–245.
28. Hendrix MJ, Seftor EA, Seftor RE, et al. Reprogramming metastatic tumour cells with embryonic microenvironments. Nat Rev Cancer 2007; 7:246–255.
29. Fiucci G, Beaucourt S, Duflaut D, et al. Siah-1b is a direct transcriptional target of p53: identification of the functional p53 responsive element in the siah-1b promoter. Proc Natl Acad Sci USA 2004; 101:3510–3515.
30. Passer BJ, Nancy-Portebois V, Amzallag N, et al. The p53-inducible TSAP6 gene product regulates apoptosis and the cell cycle and interacts with Nix and the Myt1 kinase. Proc Natl Acad Sci USA 2003; 100:2284–2289.
31. Amzallag N, Passer BJ, Allanic D, et al. TSAP6 facilitates the secretion of translationally controlled tumor protein/histamine-releasing factor via a nonclassical pathway. J Biol Chem 2004; 279:46104–46112.
32. Lespagnol A, Duflaut D, Beekman C, et al. Exosome secretion, including the DNA damage-induced p53-dependent secretory pathway, is severely compromised in TSAP6/Steap3-null mice. Cell Death Differ 2008; 15:1723–1733.
33. Cans C, Passer BJ, Shalak V, et al. Translationally controlled tumor protein acts as a guanine nucleotide dissociation inhibitor on the translation elongation factor eEF1A. Proc Natl Acad Sci USA 2003; 100:13892–13897.
34. Liu H, Peng HW, Cheng YS, et al. Stabilization and enhancement of the antiapoptotic activity of mcl-1 by TCTP. Mol Cell Biol 2005; 25:3117–3126.
35. Yang Y, Yang F, Xiong Z, et al. An N-terminal region of translationally controlled tumor protein is required for its antiapoptotic activity. Oncogene 2005; 24:4778–4788.
36. Chen SH, Wu PS, Chou CH, et al. A knockout mouse approach reveals that TCTP functions as an essential factor for cell proliferation and survival in a tissue- or cell type-specific manner. Mol Biol Cell 2007; 18:2525–2532.
37▪. Funston G, Goh W, Wei SJ, et al. Binding of translationally controlled tumour protein to the N-terminal domain of HDM2 is inhibited by Nutlin-3. PLoS One 2012; 7:e42642.

Implication of Nutlin3 in the association of TPT1/TCTP with MDM2.

38. Lin CJ, Robert F, Sukarieh R, et al. The antidepressant sertraline inhibits translation initiation by curtailing mammalian target of rapamycin signaling. Cancer Res 2010; 70:3199–3208.
39. Hsu YC, Chern JJ, Cai Y, et al. Drosophila TCTP is essential for growth and proliferation through regulation of dRheb GTPase. Nature 2007; 445:785–788.
40. Kang S, Dong SM, Kim BR, et al. Thioridazine induces apoptosis by targeting the PI3K/Akt/mTOR pathway in cervical and endometrial cancer cells. Apoptosis 2012; 17:989–997.
41. MacDonald ML, Lamerdin J, Owens S, et al. Identifying off-target effects and hidden phenotypes of drugs in human cells. Nat Chem Biol 2006; 2:329–337.
42. Sachlos E, Risueno RM, Laronde S, et al. Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells. Cell 2012; 149:1284–1297.
43. Xu W, Tamim H, Shapiro S, et al. Use of antidepressants and risk of colorectal cancer: a nested case–control study. Lancet Oncol 2006; 7:301–308.
44. Coogan PF, Strom BL, Rosenberg L. Antidepressant use and colorectal cancer risk. Pharmacoepidemiol Drug Saf 2009; 18:1111–1114.
45. Chubak J, Boudreau DM, Rulyak SJ, Mandelson MT. Colorectal cancer risk in relation to antidepressant medication use. Int J Cancer 2011; 128:227–232.
46▪. Baylot V, Katsogiannou M, Andrieu C, et al. Targeting TCTP as a new therapeutic strategy in castration resistant prostate cancer. Mol Ther 2012. [Epub ahead of print]

TPT1/TCTP is proposed as a target in prostate cancer.

47. Lo WY, Wang HJ, Chiu CW, Chen SF. miR-27b-regulated TCTP as a novel plasma biomarker for oral cancer: from quantitative proteomics to posttranscriptional study. J Proteomics 2012. [Epub ahead of print]
48. Van Es JH, van Gijn ME, Riccio O, et al. Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 2005; 435:959–963.
49. Samon JB, Castillo-Martin M, Hadler M, et al. Preclinical analysis of the gamma-secretase inhibitor PF-03084014 in combination with glucocorticoids in T-cell acute lymphoblastic leukemia. Mol Cancer Ther 2012; 11:1565–1575.
50. Tatarek J, Cullion K, Ashworth T, et al. Notch1 inhibition targets the leukemia-initiating cells in a Tal1/Lmo2 mouse model of T-ALL. Blood 2011; 118:1579–1590.
51. Huynh C, Poliseno L, Segura MF, et al. The novel gamma secretase inhibitor RO4929097 reduces the tumor initiating potential of melanoma. PLoS One 2011; 6:e25264.
52. Konishi J, Kawaguchi KS, Vo H, et al. Gamma-secretase inhibitor prevents Notch3 activation and reduces proliferation in human lung cancers. Cancer Res 2007; 67:8051–8057.
53. Ramakrishnan V, Ansell S, Haug J, et al. MRK003, a gamma-secretase inhibitor exhibits promising in vitro preclinical activity in multiple myeloma and non-Hodgkin's lymphoma. Leukemia 2012; 26:340–348.
54▪. Cook N, Frese KK, Bapiro TE, et al. Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma. J Exp Med 2012; 209:437–444.

Effect of γ secretase on pancreatic ductal adenocarcinoma.

55. Pandya K, Meeke K, Clementz AG, et al. Targeting both Notch and ErbB-2 signalling pathways is required for prevention of ErbB-2-positive breast tumour recurrence. Br J Cancer 2011; 105:796–806.
56. Takahashi C, Sheng Z, Horan TP, et al. Regulation of matrix metalloproteinase-9 and inhibition of tumor invasion by the membrane-anchored glycoprotein RECK. Proc Natl Acad Sci USA 1998; 95:13221–13226.
57. Murai R, Yoshida Y, Muraguchi T, et al. A novel screen using the Reck tumor suppressor gene promoter detects both conventional and metastasis-suppressing anticancer drugs. Oncotarget 2010; 1:252–264.

p53; sertraline; thioridazine; TPT1/TCTP; tumor reversion

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