Bax/Bak-independent mitochondrial depolarization and reactive oxygen species induction by sorafenib overcome resistance to apoptosis in renal cell carcinoma.
Renal cell carcinoma (RCC) is polyresistant to chemo- and radiotherapy and 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 to TRAIL-induced apoptosis, in particular by down-regulation 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 down-regulation. Instead, sorafenib induces rapid dissipation of the mitochondrial membrane potential (ΔΨm) that is accompanied by the accumulation of reactive oxygen species (ROS). Loss of ΔΨmand 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 ΔΨmbreakdown 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.
From the Department of Hematology, Oncology, and Tumor Immunology, University Medical Center Charité, Campus Berlin-Buch, Humboldt University, Berlin, Germany.|the German Cancer Consortium and German Cancer Research Center, Im Neuenheimer Feld, 69120 Heidelberg, Germany.
Bernhard
B
Gillissen
From the Department of Hematology, Oncology, and Tumor Immunology, University Medical Center Charité, Campus Berlin-Buch, Humboldt University, Berlin, Germany.|the German Cancer Consortium and German Cancer Research Center, Im Neuenheimer Feld, 69120 Heidelberg, Germany.
Anja
A
Richter
From the Department of Hematology, Oncology, and Tumor Immunology, University Medical Center Charité, Campus Berlin-Buch, Humboldt University, Berlin, Germany.
Antje
A
Richter
the Institute of Physiology and Experimental Clinical Research Center, University Medical Center Charité, 13125 Berlin, Germany.
Robert
R
Preissner
the German Cancer Consortium and German Cancer Research Center, Im Neuenheimer Feld, 69120 Heidelberg, Germany.|the Interfaculty Institute for Biochemistry, University of Tübingen, Hoppe-Seyler-Strasse 4, 72076 Tübingen, Germany, and.
Klaus
K
Schulze-Osthoff
the German Cancer Consortium and German Cancer Research Center, Im Neuenheimer Feld, 69120 Heidelberg, Germany.|the Interfaculty Institute for Biochemistry, University of Tübingen, Hoppe-Seyler-Strasse 4, 72076 Tübingen, Germany, and.
Frank
F
Essmann
From the Department of Hematology, Oncology, and Tumor Immunology, University Medical Center Charité, Campus Berlin-Buch, Humboldt University, Berlin, Germany, pdaniel@mdc-berlin.de.|the German Cancer Consortium and German Cancer Research Center, Im Neuenheimer Feld, 69120 Heidelberg, Germany.|Clinical and Molecular Oncology, Max Delbrück Center for Molecular Medicine, 13125 Berlin-Buch, Germany.
Peter T
PT
Daniel
D017209:Apoptosis; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D005434:Flow Cytometry; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011487:Protein Conformation; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D000077157:Sorafenib; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C494772:BAK1 protein, human; C494826:BAX protein, human; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010671:Phenylurea Compounds; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D009536:Niacinamide; D000077157:Sorafenib; C505530:CASP8 protein, human; D053181:Caspase 8
B cell lymphoma 2 (Bcl-2) family; Bak; Bax; Trail; apoptosis; cancer; drug resistance; reactive oxygen species (ROS); sorafenib