Ibuprofen-mediated Reduction of Hypoxia-inducible Factors HIF-1α and HIF-2α in Prostate Cancer Cells

• Published in: Clinical cancer research Vol. 9; no. 8; pp. 3150 - 3157
• Main Authors: PALAYOOR, Sanjeewani T, TOFILON, Philip J, COLEMAN, C. Norman
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.08.2003
• Subjects: Antineoplastic agents; Biological and medical sciences; Chemotherapy; Medical sciences; Pharmacology. Drug treatments; Antineoplastic agent; Human; Prostaglandin-endoperoxide synthase; Urinary system disease; Prostate disease; Enzyme; Enzyme inhibitor; Malignant tumor; Gene expression; In vitro; Biological activity; Non steroidal antiinflammatory agent; Gene; Hypoxia inducible factor; Ibuprofen; Established cell line; Arylpropionic acid derivatives; Transcription factor HIF1; Oxidoreductases; Mechanism of action; Male genital diseases; Prostate; Tumor cell
• ISSN: 1078-0432; 1557-3265

Purpose: Hypoxia-inducible factors HIF-1α and HIF-2α are considered to be potential targets for antineoplastic therapy because they regulate the expression of genes that contribute to tumor cell survival, aggressiveness, and angiogenesis. Nonsteroidal anti-inflammatory drugs (NSAIDs) have gained considerable interest as anticancer agents because of their cytotoxic and antiangiogenic properties. The aim of this study was to investigate whether NSAIDs inhibit HIFs and HIF-regulated gene expression in prostate cancer cells. Experimental Design: PC3 and DU-145 cells were treated with ibuprofen (Ibu) and other NSAIDs under normoxic and hypoxic (95% N 2 , 5% CO 2 ; <10 ppm O 2 ) conditions. The effect of NSAIDs on HIF proteins was analyzed by Western blot analysis. HIF-regulated proteins, vascular endothelial growth factor (VEGF) and glucose transporter-1 (Glut-1), were analyzed by ELISA and Western blot analysis, respectively. Results: Exposure of PC3 and DU-145 cells to hypoxic condition up-regulated HIF-1α and HIF-2α proteins. Treatment with Ibu under normoxic and hypoxic conditions reduced the level of HIF-1α and HIF-2α. Ibu-mediated down-regulation of HIFs was associated with down-regulation of HIF-regulated proteins VEGF and Glut-1 in cells exposed to hypoxia. Other nonspecific NSAIDs, diclofenac and ketorolac, also inhibited HIF-1α and HIF-2α. The reduction in HIFs was observed in PC3 cells that expressed cyclooxygenase-2 (COX-2) protein as well as in DU-145 cells, which did not express COX-2 protein. COX-2-specific inhibitor NS-398 did not inhibit HIF-1α or VEGF and GLUT-1. Conclusions: These data indicate that one of the effects of NSAIDs is to reduce HIF protein levels. The inhibition of HIFs by NSAIDs was COX-2 independent.