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

Takahiro Isono; Tokuhiro Chano; Tetsuya Yoshida; Susumu Kageyama; Akihiro Kawauchi; Junji Yonese; Takeshi Yuasa

doi:10.18632/oncotarget.25214

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Research Papers:

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

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Oncotarget. 2018; 9:23091-23101. https://doi.org/10.18632/oncotarget.25214

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Takahiro Isono _, Tokuhiro Chano, Tetsuya Yoshida, Susumu Kageyama, Akihiro Kawauchi, Junji Yonese and Takeshi Yuasa

Abstract

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

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.

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Research Papers:

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

Abstract