Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 292, Issue 16, Pages 6478-6492Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M116.754184
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Funding
- Stiftung Urologische Forschung Berlin
- Deutsche Krebshilfe
- Deutsches Konsortium fur Translationale Krebsforschung (DKTK) - Deutsches Krebsforschungszentrum
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Renal cell carcinoma (RCC) is polyresistant to chemo-and radiotherapy and biologicals, including TNF-related apoptosisinducing ligand (TRAIL). Sorafenib, a multikinase inhibitor approved for the treatment of RCC, has been shown to sensitize cancer cells to 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 rapid dissipation of the mitochondrial membrane potential (Delta psi m) that is accompanied by the accumulation of reactive oxygen species (ROS). Loss of Delta psi m and ROS production induced by sorafenib are independent of caspase activities and do not depend on the presence of the proapoptotic Bcl-2 family proteins Bax or Bak, indicating that both events are functionally upstream 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 Delta psi 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.
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