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Screening for genes that reprogram cancer cells for the tumor reversion switch identified TCTP (encoding translationally controlled tumor protein) as a crucial regulator of apoptosis. Here we report a negative feedback loop between P53 and TCTP. TCTP promotes P53 degradation by competing with NUMB for binding to P53-MDM2-containing complexes. TCTP inhibits MDM2 auto-ubiquitination and promotes MDM2-mediated ubiquitination and degradation of P53. Notably, Tctp haploinsufficient mice are sensitized to P53-dependent apoptosis. In addition, P53 directly represses TCTP transcription. In 508 breast cancers, high-TCTP status associates with poorly differentiated, aggressive G3-grade tumors, predicting poor prognosis (P < 0.0005). Tctp knockdown in primary mammary tumor cells from ErbB2 transgenic mice results in increased P53 expression and a decreased number of stem-like cancer cells. The pharmacological compounds sertraline and thioridazine increase the amount of P53 by neutralizing TCTP's action on the MDM2-P53 axis. This study links TCTP and P53 in a previously unidentified regulatory circuitry that may underlie the relevance of TCTP in cancer. [ABSTRACT FROM AUTHOR]

How cells become malignant has preoccupied scientists for over a century. However, the converse question is also valid: are tumour cells capable of reverting from their malignant state? Askanazy's studies in 1907 indicated that teratoma cells could differentiate into normal somatic tissues and current evidence indicates that some tumour cells have acquired the molecular circuitry that results in the negation of chromosomal instability, translocations, oncogene activation and loss of tumour suppressor genes. Studying these extremely rare events of tumour reversion and deciphering these pathways, which involve SIAH1, presenilin 1, TSAP6 and translationally controlled tumour protein (TCTP), could lead to new avenues in cancer treatment. [ABSTRACT FROM AUTHOR]

By analyzing the gene expression profile between tumor cells and revertant counterparts that have a suppressed malignant pheno-type, we previously reported a significant down-regulation of translationally controlled tumor protein (TCTP) in the revertants. In the present study, we derived, by using the H1 parvovirus as a selective agent revertants from three major solid cancers: colon, lung, and melanoma cell lines. These cells have a strongly sup- pressed malignant phenotype both in vitro and in vivo. The level of TCTP is decreased in most of the revertants. To verify whether inhibition of TCTP expression induces changes in the malignant phenotype, in the classical, well established model of "flat reversion," v-src-transformed NIH3T3 cells were transfected with anti-sense TCTP. By inhibiting the expression of TCTP, the number of revertant cells was raised to 30%, instead of the reported rate for spontaneous flat revertants of 10-6. Because Tap encodes for a histamine-releasing factor, we tested the hypothesis that inhibitors of the histaminic pathway could be effective against tumor cells. We show that some antihistaminic compounds (hydroxyzine and promethazine) and other pharmacological compounds with a related structure (including thioridazine and sertraline) kill tumor cells and significantly decrease the level of TCTP. All together, these data suggest that with tumor reversion used as a working model, TaP was identified as a target and drugs were selected that decrease its expression and kill tumor cells. [ABSTRACT FROM AUTHOR]

Tumor reversion is the process by which some cancer cells lose their malignant phenotype. This study was aimed at defining some of the molecular and phenotypic properties of this process. Biological models of tumor reversion were isolated from human leukemia and breast cancer cell lines by using the H-1 parvovirus as a selective agent. Differential gene expression analysis was performed between the parental malignant cells and their revertants or alternatively between these parental cells and their SIAH-1 transfectant counterparts. These SIAH-1 transfectants have a suppressed malignant phenotype and were used as a control for a viral-free system. Two hundred sixty-three genes were found to be either activated or inhibited during the reversion process, as confirmed by Northern blot analysis or quantitative PCR. Of these, 32% were differentially expressed in all systems, irrespective of whether parvovirus-selected, SIAH-1 overexpressing, or p53 mutant or wild-type cell lines were used, suggesting the existence of a universal mechanism underlying tumor reversion. Translationally Controlled Tumor Protein (tpt1/TCTP) has the strongest differential expression, down-regulated in the reversion of U937- and SIAH-1-overexpressing cells. Inhibition of TCTP expression by anti-sense cDNA or small interfering RNA molecules results in suppression of the malignant phenotype and in cellular reorganization, similar to the effect of SIAH-1. Hence, tumor reversion can be defined at the molecular level, not just as the reversal of malignant transformation, but as a biological process in its own right involving a cellular reprogramming mechanism, overriding genetic changes in cancer, by triggering an alternative pathway leading to suppression of tumorigenicity. [ABSTRACT FROM AUTHOR]