TRAP1 downregulation in human ovarian cancer enhances invasion and epithelial–mesenchymal transition

Abstract

Ovarian cancer (OC) is the second leading cause of gynecological cancer death worldwide. Although the list of biomarkers is still growing, molecular mechanisms involved in OC development and progression remain elusive. We recently demonstrated that lower expression of the molecular chaperone TRAP1 in OC patients correlates with higher tumor grade and stage, and platinum resistance. Herein we show that TRAP1 is often deleted in high-grade serous OC patients (N=579), and that TRAP1 expression is correlated with the copy number, suggesting this could be one of the driving mechanisms for the loss of TRAP1 expression in OC. At molecular level, downregulation of TRAP1 associates with higher expression of p70S6K, a kinase frequently active in OC with emerging roles in cell migration and tumor metastasis. Indeed, TRAP1 silencing in different OC cells induces upregulation of p70S6K expression and activity, enhancement of cell motility and epithelial–mesenchymal transition (EMT). Consistently, in a large cohort of OC patients, TRAP1 expression is reduced in tumor metastases and directly correlates with the epithelial marker E-Cadherin, whereas it inversely correlates with the transcription factor Slug and the matrix metallopeptidases 2 and 9. Strikingly, pharmacological inhibition of p70S6K reverts the high motility phenotype of TRAP1 knock-down cells. However, although p70S6K inhibition or silencing reduces the expression of the transcription factors Snail and Slug, thus inducing upregulation of E-Cadherin expression, it is unable to revert EMT induced by TRAP1 silencing; furthermore, p70S6K did not show any significant correlation with EMT genes in patients, nor with overall survival or tumor stage, suggesting an independent and predominant role for TRAP1 in OC progression. Altogether, these results may provide novel approaches in OC with reduced TRAP1 expression, which could be resistant to therapeutic strategies based on the inhibition of the p70S6K pathway, with potential future intervention in OC invasion and metastasis.

Gene Copy Number and Post-Transductional Mechanisms Regulate TRAP1 Expression in Human Colorectal Carcinomas

“…To our knowledge, this is the first study, which addresses the role of TRAP1 CN variation in human CRCs, showing that transcriptional mechanisms drive TRAP1 upregulation in human colorectal malignancies. A similar observation was previously obtained by our group in human ovarian carcinoma, a malignancy characterized by TRAP1 downregulation with parallel loss of its gene CN across tumor stage and development of platinum resistance [28,33]. This conclusion is supported by the higher levels of TRAP1 mRNA mostly in tumors with gain in TRAP1 CN and by the significant correlation between TRAP1 CN and TRAP1 mRNA and protein expression (this study and [5]), suggesting the relevance of transcriptional mechanisms in driving TRAP1 upregulation in selected colorectal malignancies.…”

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

“…This cancer stemness-promoting mechanism was based on TRAP1-mediated modulation of the expression of frizzled receptor ligands and β-catenin modification (ubiquitination/phosphorylation), so that TRAP1 upregulated the expression of β-catenin as well as several Wnt/β-catenin target genes [259]. On the contrary, in other investigations performed on human ovarian cancer, TRAP1 downregulation resulted in the enhancement of invasion and EMT [260]; such a discrepancy implies that cancer stemness-related activities of TRAP1 may cardinally differ in various types of tumors.…”

PIK3R3 Promotes Metastasis of Pancreatic Cancer via ZEB1 Induced Epithelial-Mesenchymal Transition

“…Some transcriptional factors could bind to the promoter region of E-Cadherin to suppress its expression, and further trigger the EMT conversion and metastasis of tumor cells, including SNAIL, SLUG, ZEB1 and ZEB2 [33, 34]. Among them, ZEB1 (characterized by the presence of 2 zinc finger clusters) is a well investigated transcriptional factor to act as a driver of EMT and cancer progression toward metastasis and invasion [35].…”