Demethylzeylasteral (T-96) Initiates Extrinsic Apoptosis Against Prostate Cancer cells by Inducing ROS-Mediated ER Stress and Suppressing Autophagic Flux

Abstract Demethylzeylasteral (T-96), a pharmacologically active triterpenoid monomer extracted from Tripterygiumwilfordii Hook F (TWHF), has been reported to exhibit anti-neoplastic effect on several types of cancer cells. However,whether it has the anti-tumour capability in human Prostate cancer (CaP)cells and what’s the precise regulatory mechanisms underlying the anti-proliferation effect of T-96 on human CaP. In the current study, T-96 exerted significant cytotoxicity to CaP cells in vitro and induced cell cycle arrest at S-phase in a dose-dependent manner. Furthermore, mechanistic investigation indicated that through inducing endoplasmic reticulum (ER) stress caused by intracellular accumulation of reactive oxygen species (ROS), T-96 significantly promoted autophagy initiation while blocked the autophagic flux and finally caused extrinsic apoptosis in CaP cells, implying that ER stress induced byT-96 initiated caspase dependent apoptosis to inhibit CaP cells. Moreover, as a novel lethal ER stress inducer, T-96 was capable to enhance the sensitivity of CaP cells to chemotherapeutic drug cisplatin. Taken together, our data implied that T-96 is a novel ER stress and autophagy modulator, and has the potential applications for CaP therapy in clinic.