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NS398 reduces hypoxia‐inducible factor (HIF)‐1α and HIF‐1 activity: Multiple‐level effects involving cyclooxygenase‐2 dependent and independent mechanisms
Author(s) -
Zhong Hua,
Willard Margaret,
Simons Jonathan
Publication year - 2004
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.20438
Subject(s) - cyclooxygenase , hypoxia inducible factors , hypoxia inducible factor 1 , hypoxia (environmental) , angiogenesis , transcription factor , protein kinase b , p70 s6 kinase 1 , biology , kinase , endocrinology , downregulation and upregulation , chemistry , medicine , signal transduction , microbiology and biotechnology , cancer research , enzyme , biochemistry , gene , organic chemistry , oxygen
Tissue hypoxia is a common feature in solid tumors. Hypoxia‐inducible factor 1 (HIF‐1) is a critical transcription factor that regulates the expression of genes encoding factors that influence tumor growth including vascular endothelial growth factor. Previous studies have demonstrated that post‐transcriptional modification events are important for regulation of HIF‐1α protein expression and HIF‐1 transcriptional activity. Prostaglandin E 2 (PGE 2 ), a major end product of the cyclooxygenase‐2 (COX‐2) enzyme, induces the basal and hypoxia‐induced nuclear relocalization of HIF‐1α. This is suppressed by NS398, a COX‐2 selective inhibitor. NS398 also inhibits hypoxia‐induced angiogenesis, which may be mediated by the inhibition of HIF‐1 function in a COX‐2‐dependent manner. Here, we show that NS398 reduces HIF‐1α and HIF‐1 transcriptional function in both COX‐2 positive PC‐3 cells and COX‐2 negative HCT116 cells under normoxic and hypoxic conditions. On the one hand, NS398 decreases the expression of HIF‐1α mRNA and reduces HIF‐1α synthesis in a COX‐2/PGE 2 dependent way, which can be restored by addition of exogenous PGE 2 that activates the phosphatidylinositol 3‐kinase/AKT/p70 s6k signaling pathway. On the other hand, NS398 accelerates HIF‐1α degradation by moderately increasing ubiquitination and remarkably promoting the clearance of ubiquitylated protein, an effect most likely independent of COX‐2/PGE 2 since exogenous PGE 2 fails to reverse it. Finally, NS398 decreases hypoxia‐induced shifted form of HIF‐1α and attenuates HIF‐1 activation in greater extent under hypoxic than normoxic conditions. These data not only confirm the inhibitory effect of NS398 on HIF‐1α and HIF‐1 transcriptional activity but also demonstrate that such an effect occurs at multiple levels involving both COX‐2 dependent and independent mechanisms. © 2004 Wiley‐Liss, Inc.