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

// Takahiro Isono 1 , Tokuhiro Chano 2 , Tetsuya Yoshida 3 , Susumu Kageyama 3 , Akihiro Kawauchi 3 , Junji Yonese 4 and Takeshi Yuasa 4 1 Central Research Laboratory, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan 2 Department of Clinical Laboratory Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan 3 Department of Urology, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan 4 Department of Urology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan Correspondence to: Takahiro Isono, email: isono@belle.shiga-med.ac.jp Keywords: tumor necrosis factor related apoptosis-induced ligand; hypoxia inducible factor 2-alpha; cellular FLICE (FADD-like IL-1 beta-converting enzyme)-inhibitory protein; renal cell carcinomas; apoptosis Received: November 15, 2017      Accepted: April 05, 2018      Published: May 01, 2018 ABSTRACT 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.