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COX‐2‐dependent stabilization of survivin in non‐small cell lung cancer
Author(s) -
Krysan Kostyantyn,
Merchant Farrukh H.,
Zhu Li,
Dohadwala Mariam,
Luo Jie,
Lin Ying,
HeuzeVourc'h Nathalie,
Põld Mehis,
Seligson David,
Chia David,
Goodglick Lee,
Wang Hejing,
Strieter Robert,
Sharma Sherven,
Dubinett Steven
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.03-0369fje
Subject(s) - survivin , cancer research , apoptosis , angiogenesis , biology , cell , tumor promotion , cell culture , downregulation and upregulation , cancer , carcinogenesis , gene , biochemistry , genetics
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 PGE 2 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.