Upregulation of TWIST in prostate cancer and its implication as a therapeutic target

Abstract

Androgen independent and metastatic prostate cancer is the main obstacle in the treatment of this cancer. Unlike majority of solid cancers, prostate cancer usually shows poor response to chemotherapeutic drugs. In this study, we have demonstrated a potential novel target, TWIST, a highly conserved bHLH protein, in the treatment of prostate cancer. Using malignant and non-malignant prostate tissues, we found that TWIST was highly expressed in majority (90%) of prostate cancer tissues but only in small percentage (6.7%) of Benign Prostate Hyperplasia (BPH). In addition, the TWIST expression levels were positively correlated with Gleason grading, indicating its role in the development and progression of prostate cancer. Furthermore, downregulation of TWIST through small RNA interference (RNAi) in androgen independent prostate cancer cells resulted in increased sensitivity to the anticancer drug taxol-induced cell death, which was associated with decreased Bcl:Bax ratio leading to activation of the apoptosis pathway. More importantly, inactivation of TWIST suppressed metastatic ability of androgen independent prostate cancer cells which was correlated with morphological and molecular changes associated with mesenchymal to epithelial transition (MET). In contrast, ectopic expression of TWIST in androgen dependent prostate cancer cells resulted in suppression of taxol-induced apoptosis and reversed the MET phenotype. Our results identified TWIST as a critical regulator of androgen independent prostate cancer growth and suggested a potential therapeutic approach to inhibit the growth and metastasis of androgen independent prostate cancer through targeting the TWIST gene.