title: E1A sensitizes cancer cells to TRAIL-induced apoptosis through enhancement of caspase activation.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis of cancer cells. Sensitization of cancer cells to TRAIL, particularly TRAIL-resistant cancer cells, could improve the effectiveness of TRAIL as an anticancer agent. The adenovirus type 5 E1A that associates with anticancer activities including sensitization to apoptosis induced by tumor necrosis factor is currently being tested in clinical trials. In this study, we investigated the sensitivity to TRAIL in the E1A transfectants ip1-E1A2 and 231-E1A cells and the parental TRAIL-resistant human ovarian cancer SKOV3.ip1 and TRAIL-sensitive human breast cancer MDA-MB-231 cells. The results indicated that the percentage of TRAIL-induced apoptotic cells was significantly higher in the E1A transfectants of both cell lines than it was in the parental cell lines. To further investigate the cellular mechanism of this effect, we found that E1A enhances TRAIL-induced activation of caspase-8, caspase-9, and caspase-3. Inhibition of caspase-3 activity by a specific inhibitor, Z-DEVD-fmk, abolished TRAIL-induced apoptosis. In addition, E1A enhanced TRAIL expression in ip1-E1A2 cells, but not in 231-E1A cells, and the anti-TRAIL neutralizing antibody N2B2 blocked the E1A-mediated bystander effect in vitro. Taken together, these results suggest that E1A sensitizes both TRAIL-sensitive and TRAIL-resistant cancer cells to TRAIL-induced apoptosis, which occurs through the enhancement of caspase activation; activation of caspase-3 is required for TRAIL-induced apoptosis; and E1A-induced TRAIL expression is involved in the E1A-mediated bystander effect. Combination of E1A and TRAIL could be an effective treatment for cancer.
authors.affiliation: Department of Molecular and Cellular Oncology, Unit 108, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
authors.forename: Ruping
authors.initials: R
authors.lastname: Shao
authors.forename: Dung-Fang
authors.initials: DF
authors.lastname: Lee
authors.forename: Yong
authors.initials: Y
authors.lastname: Wen
authors.forename: Yi
authors.initials: Y
authors.lastname: Ding
authors.forename: Weiya
authors.initials: W
authors.lastname: Xia
authors.forename: Bo
authors.initials: B
authors.lastname: Ping
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Bill
authors.initials: B
authors.lastname: Spohn
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
mesh_terms: D017500:Adenovirus E1A Proteins / Q000235:genetics* / Q000378:metabolism; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms / Q000628:therapy; D024201:Bystander Effect; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000628:therapy*; D011994:Recombinant Proteins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D017500:Adenovirus E1A Proteins; D000906:Antibodies; D051017:Apoptosis Regulatory Proteins; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D008562:Membrane Glycoproteins; D009842:Oligopeptides; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases