title: Indomethacin promotes apoptosis in gastric cancer cells through concomitant degradation of Survivin and Aurora B kinase proteins.
abstract: Regular usage of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with reduced incidence of a variety of cancers. The molecular mechanisms underlying these chemopreventive effects remain poorly understood. This current investigation showed that in gastric cancer cells: (1) Indomethacin treatment enhanced the degradation of chromosomal passenger proteins, Survivin and Aurora B kinase; (2) Indomethacin treatment down-regulated Aurora B kinase activity in a cell cycle-independent fashion; (3) siRNA knockdown of Survivin level promoted Aurora B kinase protein degradation, and vice versa; (4) ectopic overexpression of Survivin blocked reduction of Aurora B kinase level and activity by indomethacin treatment, and vice versa; (5) siRNA knockdown of Aurora B kinase level and AZD1152 inhibition of its activity induced apoptosis, and overexpression of Aurora B kinase inhibited indomethacin-induced apoptosis; (6) indomethacin treatment reduced Aurora B kinase level, coinciding with reduction of Survivin level and induction of apoptosis, in KATO III and HT-29 cells, and in mouse gastric mucosa. A role for Aurora B kinase function in NSAID-induced apoptosis was not previously explored. Thus this report provides better understanding of the molecular mechanisms underlying the anti-cancer effect of NSAIDs by elucidating a significant role for Aurora B kinase in indomethacin-induced apoptosis.
authors.affiliation: Department of Veterans Affairs Medical Center, 5901 E 7th st., Long Beach, CA, 90822-5201, USA, skchiou@yahoo.com.
authors.forename: Shiun-Kwei
authors.initials: SK
authors.lastname: Chiou
authors.forename: Neil
authors.initials: N
authors.lastname: Hoa
authors.forename: Amy
authors.initials: A
authors.lastname: Hodges
authors.forename: Lishen
authors.initials: L
authors.lastname: Ge
authors.forename: Martin R
authors.initials: MR
authors.lastname: Jadus
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D064107:Aurora Kinase B / Q000235:genetics / Q000378:metabolism*; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor / Q000187:drug effects; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D010755:Organophosphates / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology*; D000077022:Survivin
chemical_list: C520647:2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D010755:Organophosphates; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077022:Survivin; D064107:Aurora Kinase B; D007213:Indomethacin