COX-2-dependent stabilization of survivin in non-small cell lung cancer.
Elevated tumor cyclooxygenase 2 (COX-2) expression is associated with increased angiogenesis, tumor invasion and promotion of tumor cell resistance to apoptosis. The mechanism(s) by which COX-2 exerts its cytoprotective effects are not completely understood but may be due to an imbalance of pro- and anti-apoptotic gene expression. To analyze COX-2-dependent gene expression and apoptosis, we created cell lines constitutively expressing COX-2 cDNA in sense and antisense orientations. Whereas COX-2 sense cells have significantly heightened resistance to radiation and drug-induced apoptosis, COX-2 antisense cells are highly sensitive to apoptosis induction. We found that the expression of the anti-apoptotic protein survivin correlated positively with COX-2 expression. A COX-2-dependent modulation of survivin ubiquitination led to its stabilization in COX-2 overexpressing cells, and this effect was replicated by exogenous PGE2 treatment of parental tumor cells. In contrast to previous studies in other cell types, in nonsmall cell lung cancer cells survivin was expressed in a cell cycle-independent manner. When established in SCID mice in vivo, COX-2 antisense-derived tumors had significantly decreased survivin levels while COX-2 sense-derived tumors demonstrated elevated levels compared with controls. In accord with these findings, survivin and COX-2 were frequently upregulated and co-expressed in human lung cancers in situ.
Krysan
Kostyantyn
K
UCLA Lung Cancer Research Program, Jonsson Comprehensive Cancer Center, Los Angeles, California, USA.
Merchant
Farrukh H
FH
Zhu
Li
L
Dohadwala
Mariam
M
Luo
Jie
J
Lin
Ying
Y
Heuze-Vourc'h
Nathalie
N
Põld
Mehis
M
Seligson
David
D
Chia
David
D
Goodglick
Lee
L
Wang
Hejing
H
Strieter
Robert
R
Sharma
Sherven
S
Dubinett
Steven
S
D000818:Animals; D016375:Antisense Elements (Genetics); D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D000077022:Survivin; D014452:Ubiquitins / Q000378:metabolism; D015854:Up-Regulation
D016375:Antisense Elements (Genetics); C107489:BIRC5 protein, human; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D014452:Ubiquitins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone