COX-2-dependent stabilization of survivin in non-small cell lung cancer

被引:112
作者
Krysan, K
Merchant, FH
Zhu, L
Dohadwala, M
Luo, J
Lin, Y
Heuze-Vourc'h, N
Pold, M
Seligson, D
Chia, D
Goodglick, L
Wang, HJ
Strieter, R
Sharma, S
Dubinett, S
机构
[1] Univ Calif Los Angeles, David Geffen Sch Med, Div Pulm & Crit Care Med, Los Angeles, CA 90095 USA
[2] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Lung Canc Res Program, Los Angeles, CA 90024 USA
[3] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA
[4] Univ Calif Los Angeles, Defined Tumor Marker Evaluat Ctr, Los Angeles, CA 90024 USA
关键词
cyclooxygenase; 2; prostaglandin; NSCLC cells;
D O I
10.1096/fj.03-0369fje
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:205 / 206
页数:2
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