title: Roles of NF-kappaB and 26 S proteasome in apoptotic cell death induced by topoisomerase I and II poisons in human nonsmall cell lung carcinoma.
abstract: Activation of signaling pathways after DNA damage induced by topoisomerase (topo) poisons can lead to cell death by apoptosis. Treatment of human nonsmall cell lung carcinoma (NSCLC-3 or NSCLC-5) cells with the topo I poison SN-38 or the topo II poison etoposide (VP-16) leads to activation of NF-kappaB before induction of apoptosis. Inhibiting the degradation of IkappaBalpha by pretreatment with the proteasome inhibitor MG-132 significantly inhibited NF-kappaB activation and apoptosis but not DNA damage induced by SN-38 or VP-16. Transfection of NSCLC-3 or NSCLC-5 cells with dominant negative mutant IkappaBalpha (mIkappaBalpha) inhibited SN-38 or VP-16 induced transcription and DNA binding activity of NF-kappaB without altering drug-induced apoptosis. Regulation of apoptosis by mitochondrial release of cytochrome c and activation of pro-caspase 9 followed by cleavage of poly(ADP-ribose) polymerase by effector caspases 3 and 7 was similar in neo and mIkappaBalpha cells treated with SN-38 or VP-16. In contrast to pretreatment with MG-132, exposure to MG-132 after SN-38 or VP-16 treatment of neo or mIkappaBalpha cells decreased cell cycle arrest in the S/G2 + M fraction and enhanced apoptosis compared with drug alone. In summary, apoptosis induced by topoisomerase poisons in NSCLC cells is not mediated by NF-kappaB but can be manipulated by proteasome inhibitors.
authors: Experimental Therapeutics Program, Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
authors: M
authors: M
authors: Tabata
authors: R
authors: R
authors: Tabata
authors: D R
authors: DR
authors: Grabowski
authors: R M
authors: RM
authors: Bukowski
authors: M K
authors: MK
authors: Ganapathi
authors: R
authors: R
authors: Ganapathi
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002945:Cisplatin / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins; D000077146:Irinotecan; D007976:Leupeptins / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000502:physiology*; D017239:Paclitaxel / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D007976:Leupeptins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D000072000:NF-KappaB Inhibitor alpha; D005047:Etoposide; D000077146:Irinotecan; D004247:DNA; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D017239:Paclitaxel; D002945:Cisplatin; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D002166:Camptothecin