title: Sulindac-derived reactive oxygen species induce apoptosis of human multiple myeloma cells via p38 mitogen activated protein kinase-induced mitochondrial dysfunction.
abstract: Non-steroidal anti-inflammatory drugs are well known to induce apoptosis of cancer cells independent of their ability to inhibit cyclooxygenase-2, but the molecular mechanism for this effect has not yet been fully elucidated. The purpose of this study was to elucidate the potential signaling components underlying sulindac-induced apoptosis in human multiple myeloma (MM) cells. We found that sulindac induces apoptosis by promoting ROS generation, accompanied by opening of mitochondrial permeability transition pores, release of cytochrome c and apoptosis inducing factor from mitochondria, followed by caspase activation. Bcl-2 cleavage and down-regulation of the inhibitor of apoptosis proteins (IAPs) family including cIAP-1/2, XIAP, and survivin, occurred downstream of ROS production during sulindac-induced apoptosis. Forced expression of survivin and Bcl-2 blocked sulindac-induced apoptosis. Most importantly, sulindac-derived ROS activated p38 mitogen-activated protein kinase and p53. SB203580, a p38 mitogen-activated protein kinase inhibitor, and RNA inhibition of p53 inhibited the sulindac-induced apoptosis. Furthermore, p53, Bax, and Bak accumulated in mitochondria during sulindac-induced apoptosis. All of these events were significantly suppressed by SB203580. Our results demonstrate a novel mechanism of sulindac-induced apoptosis in human MM cells, namely, accumulation of p53, Bax, and Bak in mitochondria mediated by p38 MAPK activation downstream of ROS production.
authors.affiliation: Laboratory of Functional Genomics, Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-Dong, Nowon-Ku, Seoul, 139-706, Republic of Korea.
authors.forename: Sung-Keum
authors.initials: SK
authors.lastname: Seo
authors.forename: Hyung-Chahn
authors.initials: HC
authors.lastname: Lee
authors.forename: Sang-Hyeok
authors.initials: SH
authors.lastname: Woo
authors.forename: Hyeon-Ok
authors.initials: HO
authors.lastname: Jin
authors.forename: Doo-Hyun
authors.initials: DH
authors.lastname: Yoo
authors.forename: Su-Jae
authors.initials: SJ
authors.lastname: Lee
authors.forename: Sungkwan
authors.initials: S
authors.lastname: An
authors.forename: Tae-Boo
authors.initials: TB
authors.lastname: Choe
authors.forename: Myung-Jin
authors.initials: MJ
authors.lastname: Park
authors.forename: Seok-Il
authors.initials: SI
authors.lastname: Hong
authors.forename: In-Chul
authors.initials: IC
authors.lastname: Park
authors.forename: Chang-Hun
authors.initials: CH
authors.lastname: Rhee
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013467:Sulindac / Q000494:pharmacology*; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C494772:BAK1 protein, human; C494826:BAX protein, human; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D000077022:Survivin; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D013467:Sulindac; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases