The Transcriptional Factor ZEB1 Promotes Chemoresistence In Prostate Cancer Cell Line

It has been reported that one of the factors that promotes tumoral progress is the abnormal activation of the Epithelial-Mesenchymal Transition (EMT) program which has been associated with chemoresistant phenotype of tumoral cells . The transcription factor ZEB1, one of the key EMT activators, has recently been related to resistance to docetaxel, the main chemotherapeutic used in prostate cancer treatment. However, the mechanisms involved in this protective effect are still unclear. In a previous work we demonstrated that ZEB1 expression induced an EMT-like phenotype in prostate cancer cell lines. In the present work we used the prostate cancer cell lines 22Rv1 and DU145 to understand the effect of ZEB1 expression on resistance to docetaxel and its possible mechanisms in prostate cancer. The results showed that ZEB1 overexpression of ZEB1 conferred 22Rv1 cells a higher resistance to docetaxel while its silencing made DU145 cells more sensitive to it. Analysis of resistance markers showed no presence of ABCB1, and no changes in ABCG2, ABCC10 and class III β-tubulin. However, a correlation between ZEB1 and ABCC1 and ABCC4 expression was observed. Moreover, ABCC4 inhibition, using MK571, resensitized cells with ZEB1 overexpression to docetaxel treatment. Additionally, ZEB1 expression also correlated with a lower apoptotic response to the drug, characterized by a low Bcl2, high Bax expression and high active caspase 3. The response to docetaxel in our model appeared to be mediated mainly by the activation of the apoptotic death program. Our results show that ZEB1 could be a modulator of several mechanisms of resistance to docetaxel in prostate cancer making it a possible marker for chemotherapy response.

Grant: FONDECYT N° 1151214 (HC), FONDECYT N° 1140417 (EC). CONICYT scholarship N° 21140772 (OO).