Hypoxia and low glucose differentially augments TRAIL-induced apoptotic death.
Tumor microenvironment, which is characterized by hypoxia, low-glucose concentrations, high-lactate concentrations, low-extracellular pH, can alter the therapeutic response in tumors. In this study, we investigated whether hypoxia affects TRAIL-induced apoptotic death. When human prostate adenocarcinoma DU-145 cells were treated with 50 ng/mL TRAIL or hypoxia for 4 h, the survival was 45.7 and 32.5%, respectively. The combination of TRAIL and hypoxia synergistically increased cell death. Similar results were observed in human prostate adenocarcinoma LNCaP cells. Western blot analysis showed that the hypoxia augmented TRAIL-induced PARP cleavage as well as the activation of caspase-8 and caspase-3, but not caspase-9. Unlike hypoxia, low glucose promoted caspase-9 activation during TRAIL treatment. These results suggest that hypoxia or low glucose-augmented TRAIL cytotoxicity is mediated through the mitochondria-independent pathway or -dependent pathway, respectively.
Lee
Yong J
YJ
Department of Surgery and Pharmacology, School of Medicine, University of Pittsburgh, Hillmam Cancer Center, Pittsburgh, Pennsylvania 15213, USA. leeyj@msx.upmc.edu
Moon
Mi-Sun
MS
Kwon
Seok J
SJ
Rhee
Juong G
JG
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D000860:Hypoxia; D015151:Immunoblotting; D008562:Membrane Glycoproteins / Q000378:metabolism*; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; D005947:Glucose