title: Mitogen-activated protein kinases mediate arsenic-induced down-regulation of survivin in human lung adenocarcinoma cells.
abstract: Survivin is a member of the inhibitors of apoptosis protein (IAP) family and is highly expressed in various cancer cells. However, the molecular mechanisms regulating survivin expression remain unclear. In this study, we investigated the role of mitogen-activated protein kinases (MAPKs) in regulating survivin in the human lung adenocarcinoma cell line H1355 in response to arsenic trioxide (As(3+)). Our data indicated that As(3+) induced cytotoxicity accompanied by down-regulation of survivin, cleavage of Poly ADP-ribosyl polymerase (PARP) and activations of MAPKs, including ERK1/2, p38 and c-jun N-terminal kinase (JNK). We found that blockage of p38 or JNK activation attenuated the As(3+)-induced survivin down-regulation and PARP cleavage with significant reversal of cell viability, however, by only 5-8%. On the other hand, the MEK inhibitor PD098059 or the ubiquitin-proteasome inhibitor MG-132 exhibited little effect on survivin down-regulation and PARP cleavage induced by As(3+). In this study, we demonstrated that As(3+) could down-regulate survivin via activations of p38 and JNK in an ubiquitin-proteasome independent pathway and lead to cytotoxicity and apoptosis in the human lung adenocarcinoma cell line H1355.
authors.affiliation: Division of Environmental Health and Occupational Medicine, National Health Research Institutes, 35 Keyan Road, Miaoli County 350, Zhunan Town, Taiwan.
authors.forename: Yahsin
authors.initials: Y
authors.lastname: Cheng
authors.forename: Louis W
authors.initials: LW
authors.lastname: Chang
authors.forename: Tsui-Chun
authors.initials: TC
authors.lastname: Tsou
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004336:Drug Antagonism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D010087:Oxides / Q000633:toxicity*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D000077022:Survivin
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D010087:Oxides; D000077022:Survivin; D011065:Poly(ADP-ribose) Polymerases; D020928:Mitogen-Activated Protein Kinases; D000077237:Arsenic Trioxide