Tetrandrine (TET) Induces Death Receptors: Apo Trail R1 (DR4) and Apo Trail R2 (DR5) and sensitizes Prostate Cancer Cells to TRAIL induced apoptosis

TNF-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in cancer cells, but not in normal cells, as such is a promising therapeutic agent. However, therapeutic resistance limits its clinical use in many malignancies including prostate cancer (PCa). Strategies to sensitize cancer cells to TRAIL are urgently needed. We demonstrate here that small-molecule Tetrandrine (TET) potentially sensitizes previously resistant (LNCaP and C4-2B cells) and mildly sensitive (PC3 cells) PCa cells to TRAIL- induced apoptosis, and they do so by up-regulating mRNA expression and protein levels of death receptors Apo Trail R1 (DR4) and Apo Trail R2 (DR5). Using shRNA knockdown, we show critical requirement of DR4 and DR5 in sensitization of PCa cells to TRAIL. We show that double knock down of DR4 and DR5 abrogated the apoptotic effects of TET and TRAIL. We also demonstrate that TET induced DR4 and DR5 expression is independent of p53 status. Given that loss of p53 is associated with progression of PCa to CRPC and NEPC, our results show that TET by acting as a TRAIL sensitizing agent in PCa could serve as a potential therapeutic agent in CRPC and NEPC for which there is no cure to date.

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