TRAIL and inhibitors of apoptosis are opposing determinants for NF-kappaB-dependent, genotoxin-induced apoptosis of cancer cells.
Opposing pro- and anti-apoptotic actions of TRAIL and the inhibitors of apoptosis (IAPs) contribute to the cell's decision to survive or die. We demonstrate that in H157 human lung carcinoma cells, etoposide and doxorubicin induce the NF-kappaB-dependent expression of both pro- and anti-apoptotic proteins including TRAIL and its death receptor, DR5, and IAPs. Inhibition of NF-kappaB activation in H157 cells in response to genotoxin resulted in loss of cell surface expression of TRAIL and DR5, aggressive growth and chemotherapy resistance of tumors in nude mice. Similar to the paracrine TRAIL response in H157 cells, the sensitivity of normal lung and breast epithelium and carcinomas to undergo genotoxin-induced apoptosis correlates strongly with cell surface expression of TRAIL. Suppression of TRAIL signaling by expression of the TRAIL decoy receptor, DcR1, confers chemoresistance to cancer cells. These findings demonstrate that TRAIL signaling via its death receptors is a significant contributor to genotoxin-induced apoptosis in human epithelial carcinomas.
Spalding
Aaron C
AC
Department of Pharmacology, University of Colorado Cancer Center, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, Colorado, CO 80262, USA.
Jotte
Robert M
RM
Scheinman
Robert I
RI
Geraci
Mark W
MW
Clarke
Penny
P
Tyler
Kenneth L
KL
Johnson
Gary L
GL
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms; D002294:Carcinoma, Squamous Cell; D003001:Cloning, Molecular; D016172:DNA Fingerprinting; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000633:toxicity*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D020672:I-kappa B Proteins; D007700:Kinetics; D008175:Lung Neoplasms; D008562:Membrane Glycoproteins / Q000235:genetics*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D005047:Etoposide