TRAIL sensitizes for ionizing irradiation-induced apoptosis through an entirely Bax-dependent mitochondrial cell death pathway.
The death ligand TRAIL has been suggested as a suitable biological agent for the selective induction of cell death in cancer cells. Moreover, TRAIL synergizes with DNA-damaging therapies such as chemotherapeutic drugs or ionizing irradiation (IR). Here, we show that synergy of TRAIL and IR, that is, crosssensitization between TRAIL and IR for induction of apoptosis, entirely depends on Bax proficiency in human DU145 and HCT116 carcinoma cells. DU145 prostate carcinoma cells that have lost Bax protein expression due to mutation fail to activate caspase-3 and -9 when exposed to TRAIL and IR. In contrast, TRAIL sensitized for IR-induced apoptosis and vice versa upon reconstitution of Bax expression. Notably, both DU145 and HCT116 still express significant levels of the multidomain proapoptotic Bcl-2 homolog Bak. This indicates that Bak is not sufficient to mediate crosssensitization and synergism between IR and TRAIL. These data clearly establish distinct roles for Bax and Bak in linking the TRAIL death receptor pathway to the mitochondrial apoptosis signaling cascade upon DNA damage by IR.
Wendt
Jana
J
Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Humboldt University, Berlin, Germany.
von Haefen
Clarissa
C
Hemmati
Philipp
P
Belka
Claus
C
Dörken
Bernd
B
Daniel
Peter T
PT
D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects*; D051017:Apoptosis Regulatory Proteins; D016923:Cell Death / Q000528:radiation effects; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D005720:Gamma Rays; D006801:Humans; D007425:Intracellular Membranes / Q000502:physiology; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D008928:Mitochondria / Q000502:physiology* / Q000528:radiation effects; D011471:Prostatic Neoplasms; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism* / Q000528:radiation effects; D015398:Signal Transduction / Q000528:radiation effects; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D051028:bcl-2-Associated X Protein
D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein