Tanshinone IIA enhances the effects of TRAIL by downregulating survivin in human ovarian carcinoma cells

• Published in: Phytomedicine (Stuttgart) 2015-09, Vol.22 (10), p.929-938
• Main Authors: Lin, Jyun-Yi, Ke, Yu-Min, Lai, Jui-Sheng, Ho, Tsing-Fen
• Format: Article
• Language: English
• Subjects: Analysis; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Care and treatment; Cell Line, Tumor - drug effects; Diterpenes, Abietane - pharmacology; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; Humans; Inhibitor of Apoptosis Proteins - metabolism; Ovarian cancer; Ovarian Neoplasms - metabolism; p38 mitogen-activated protein kinase (p38 MAPK); Salvia; Survivin; Tanshinone IIA (TIIA); TNF-Related Apoptosis-Inducing Ligand - metabolism; Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)
• ISSN: 0944-7113; 1618-095X
• DOI: 10.1016/j.phymed.2015.06.012

Tanshinone IIA (TIIA), a diterpene quinone from the medicinal plant Salvia miltiorrhiza Bunge (Lamiaceae) was shown to possess apoptotic and TRAIL-sensitizing effects. Still, the molecular mechanisms whereby TIIA induces apoptosis remain largely unknown. The role of survivin, an inhibitor of apoptosis protein, in TIIA-induced apoptosis has never been addressed before and hence was the primary goal of this study. In this study, we explored the anticancer effect of TIIA in TOV-21G, SKOV3, and OVCAR3 ovarian carcinoma cells. Cytotoxicity was determined by MTS assay. Real-time RT-PCR and Western blotting were used to assess the mRNA and protein expression of related signaling proteins. Our results illustrated that TIIA's cytotoxic effect was caused by apoptosis with the involvement of caspases activity. Moreover, TIIA downregulated survivin in a concentration-dependent manner without affecting the expression of Bcl-2, Bcl-xL, and Bax. TIIA-induced survivin downregulation is regulated by both transcriptional processes and proteasomal degradation. Using TOV-21G cells as our cellular model, we demonstrated that TIIA-induced survivin downregulation requires p38 MAPK activation. Importantly, genetic overexpression of survivin rendered cells more resistant to TIIA, indicating an essential role of survivin downregulation in TIIA-induced apoptosis. This TRAIL sensitization effect of TIIA is ascribed to survivin downregulation because the effect was abrogated in cells that overexpressed survivin. Our findings provide new insights into the action modes of TIIA-mediated anticancer effects and further implicate a rational design for cancer therapeutic regimens by combining TIIA-sensitized TRAIL via downregulating survivin to elicit ovarian cancer cell death. [Display omitted]