Abundance of TRAIL attenuated by HIF2α and c-FLIP affects malignancy in renal cell carcinomas
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Takahiro Isono1, Tokuhiro Chano2, Tetsuya Yoshida3, Susumu Kageyama3, Akihiro Kawauchi3, Junji Yonese4 and Takeshi Yuasa4
1Central Research Laboratory, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
2Department of Clinical Laboratory Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
3Department of Urology, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
4Department of Urology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan
Takahiro Isono, email: [email protected]
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
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.
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