Abstract 730: The role of ZEB1/ZEB2 and βIII-tubulin in mediating docetaxel-resistant prostate cancer

Abstract

Abstract Docetaxel therapy is the gold standard treatment for advanced castrate-resistant prostate cancer (CRPC). However, patients either do not respond or develop resistance over time. Transcriptomic and proteomic analysis of docetaxel-resistant prostate cancer sub-lines developed by our group revealed multiple mechanisms of resistance in line with advanced disease, including over-expression of anti-apoptotic proteins and alterations of NF-KB activation. The sub-lines also demonstrated a coordinated loss and gain of epithelial and mesenchymal markers respectively; a process characteristic of Epithelial-Mesenchymal Transition (EMT). Studies have highlighted a role of EMT in prostate cancer progression, metastasis and docetaxel resistance. However, the role of EMT drivers in mediating resistance is not defined. We hypothesise EMT to be a central mechanism of apoptotic resistance in advanced docetaxel-resistant prostate cancer, representing a target for therapeutic manipulation. EMT was characterised in the PC-3 D12 and DU145 R docetaxel-resistant sub-lines through an increased invasive capacity, MMP-1 secretion and protein expression of E-cadherin transcriptional repressors ZEB1 and ZEB2, in comparison to parental cell lines. This was associated with an increased expression of βIII-tubulin; a tubulin isotype linked to taxane resistance and tumour aggressiveness. Upon treatment with the apoptotic trigger docetaxel (20nM), the PC-3 D12 and DU145 R sub-lines demonstrated significant resistance compared to parental controls. Simultaneous siRNA knockdown of ZEB1 and ZEB2 resulted in both a partial reversal in apoptotic resistance and a decrease in cell viability; this was also associated with a down-regulation of βIII-tubulin and a re-expression of E-cadherin. Our results provide evidence of the process of EMT in in vitro models of docetaxel-resistant prostate cancer, which is associated with differential susceptibility to docetaxel and is partially reversed through siRNA knockdown of the EMT drivers, ZEB1 and ZEB2. In addition, we have identified a link between EMT and βIII-tubulin in our models of docetaxel resistance. Current experiments are investigating the tissue expression of ZEB1 and βIII-tubulin in prostate cancer metastases following docetaxel therapy, which will determine the clinical relevance of EMT and βIII-tubulin as mediators of docetaxel resistance in CRPC. Citation Format: Karen Hanrahan, Maria Prencipe, Jane Bugler, Lisa Murphy, Amanda O'Neill, R. William Watson. The role of ZEB1/ZEB2 and βIII-tubulin in mediating docetaxel-resistant prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 730. doi:10.1158/1538-7445.AM2015-730