This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Palayoor, S. T. Articles by Coleman, C. N. Search for Related Content PubMed PubMed Citation Articles by Palayoor, S. T. Articles by Coleman, C. N.

Ibuprofen-mediated Reduction of Hypoxia-inducible Factors HIF-1 and HIF-2 in Prostate Cancer Cells¹

Radiation Oncology Branch, Center for Cancer Research and the Molecular Radiation Therapeutics Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, Maryland, 20892-1002

Purpose: Hypoxia-inducible factors HIF-1 and HIF-2 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% N₂, 5% CO₂; <10 ppm O₂) 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-1 and HIF-2 proteins. Treatment with Ibu under normoxic and hypoxic conditions reduced the level of HIF-1 and HIF-2. 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-1 and HIF-2. 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-1 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.

This article has been cited by other articles:

				E. J. Quann, F. Khwaja, K. H. Zavitz, and D. Djakiew The Aryl Propionic Acid R-Flurbiprofen Selectively Induces p75NTR-Dependent Decreased Survival of Prostate Tumor Cells Cancer Res., April 1, 2007; 67(7): 3254 - 3262. [Abstract] [Full Text] [PDF]

				K S Kimbro and J W Simons Hypoxia-inducible factor-1 in human breast and prostate cancer. Endocr. Relat. Cancer, September 1, 2006; 13(3): 739 - 749. [Abstract] [Full Text] [PDF]

				G. M. Woldemichael, J. R. Vasselli, R. S. Gardella, T. C. Mckee, W. M. Linehan, and J. B. McMahon Development of a Cell-Based Reporter Assay for Screening of Inhibitors of Hypoxia-Inducible Factor 2-Induced Gene Expression J Biomol Screen, September 1, 2006; 11(6): 678 - 687. [Abstract] [PDF]

				K. D. A. Beharry, H. D. Modanlou, J. Hasan, Z. Gharraee, P. Abad-Santos, J. H. Sills, A. Jan, S. Nageotte, and J. V. Aranda Comparative Effects of Early Postnatal Ibuprofen and Indomethacin on VEGF, IGF-I, and GH during Rat Ocular Development. Invest. Ophthalmol. Vis. Sci., July 1, 2006; 47(7): 3036 - 3043. [Abstract] [Full Text] [PDF]

				S. T. Palayoor, M. J. Arayankalayil, A. Shoaibi, and C. N. Coleman Radiation Sensitivity of Human Carcinoma Cells Transfected with Small Interfering RNA Targeted against Cyclooxygenase-2 Clin. Cancer Res., October 1, 2005; 11(19): 6980 - 6986. [Abstract] [Full Text] [PDF]

				T Gaber, R Dziurla, R Tripmacher, G R Burmester, and F Buttgereit Hypoxia inducible factor (HIF) in rheumatology: low O2! See what HIF can do! Ann Rheum Dis, July 1, 2005; 64(7): 971 - 980. [Abstract] [Full Text] [PDF]

				M. F. McCarty Targeting Multiple Signaling Pathways as a Strategy for Managing Prostate Cancer: Multifocal Signal Modulation Therapy Integr Cancer Ther, December 1, 2004; 3(4): 349 - 380. [Abstract] [PDF]

				S. T. Palayoor, M. A. Burgos, A. Shoaibi, P. J. Tofilon, and C. N. Coleman Effect of Radiation and Ibuprofen on Normoxic Renal Carcinoma Cells Overexpressing Hypoxia-Inducible Factors by Loss of von Hippel-Lindau Tumor Suppressor Gene Function Clin. Cancer Res., June 15, 2004; 10(12): 4158 - 4164. [Abstract] [Full Text] [PDF]