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Bax/Bak-independent mitochondrial depolarization and reactive oxygen species induction by sorafenib overcome resistance to apoptosis in renal cell carcinoma

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Item Type:Article
Title:Bax/Bak-independent mitochondrial depolarization and reactive oxygen species induction by sorafenib overcome resistance to apoptosis in renal cell carcinoma
Creators Name:Gillissen, B. and Richter, A. and Richter, A. and Preissner, R. and Schulze-Osthoff, K. and Essmann, F. and Daniel, P.T.
Abstract:Renal cell carcinoma (RCC) is polyresistant to chemo- and radiotherapy or biologicals including TNF-related apoptosis inducing ligand (TRAIL). Sorafenib, a multikinase inhibitor approved for the treatment of RCC, has been shown to sensitize cancer cells toward TRAIL-induced apoptosis, in particular by downregulation of the Bak-inhibitory Bcl 2 family protein Mcl 1. Here, we demonstrate that sorafenib overcomes TRAIL resistance in RCC by a mechanism that does not rely on Mcl 1 downregulation. Instead, sorafenib induces a rapid dissipation of the mitochondrial membrane potential (ΔΨ(m)) that is accompanied by the accumulation of reactive oxygen species (ROS). Loss of ΔΨ(m) and ROS production induced by sorafenib are independent of caspase activities and do not depend on the presence of the pro-apoptotic Bcl 2 family proteins Bax or Bak indicating that both events are functionally up-stream of the mitochondrial apoptosis signaling cascade. More intriguingly, we find that it is sorafenib-induced ROS accumulation that enables TRAIL to activate caspase 8 in RCC. This leads to apoptosis that involves activation of an amplification loop via the mitochondrial apoptosis pathway. Thus, our mechanistic data indicate that sorafenib bypasses central resistance mechanisms through a direct induction of ΔΨ(m) breakdown and ROS production. Activation of this pathway might represent a useful strategy to overcome the cell-inherent resistance to cancer therapeutics including TRAIL in multiresistant cancers such as RCC.
Keywords:Sorafenib, TRAIL Resistance, Reactive Oxygen Species (ROS), Apoptosis, B-Cell Lymphoma 2 (Bcl-2) Family, Bax, Bak, Cancer
Source:Journal of Biological Chemistry
ISSN:0021-9258
Publisher:American Society for Biochemistry and Molecular Biology (U.S.A.)
Volume:292
Number:16
Page Range:6478-6492
Date:21 April 2017
Official Publication:https://doi.org/10.1074/jbc.M116.754184
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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