Abundance of TRAIL attenuated by HIF2α and c-FLIP affects malignancy in renal cell carcinomas

Dormant cancer cells are starvation-resistant leading to problems in the management of cancer. In renal cell carcinomas (RCCs), starvation-resistant cells are resistant to various currently available therapies. However, targeting hypoxia inducible factor 2-alpha (HIF2-alpha) induces cell death in dormant-like/starvation-resistant RCCs. This study showed that the apoptotic cell death caused by tumor necrosis factor (TNF)-related apoptosis-induced ligand (TNFSF10/TRAIL) was attenuated by CASP8 and FADD-like apoptosis regulator (CFLAR/c-FLIP) following HIF2-alpha activation, despite the high expression of TRAIL in such RCCs. Knockdowns of TRAIL averted apoptotic cell death caused by HIF2-alpha inhibition in starvation-resistant RCCs. Knockdowns of both HIF2-alpha and c-FLIP augmented apoptotic cell death, whereas overexpression of c-FLIP completely averted apoptosis. In addition, high abundance of TRAIL was correlated with poor prognosis in patients with RCC, suggesting that TRAIL, followed by HIF2-alpha and c-FLIP, play a role in the survival and/or progression of malignant RCCs.