This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 Trimboli, A. J. Articles by Chilton, F. H. Search for Related Content PubMed PubMed Citation Articles by Trimboli, A. J. Articles by Chilton, F. H.

Influence of Coenzyme A-independent Transacylase and Cyclooxygenase Inhibitors on the Proliferation of Breast Cancer Cells¹

Departments of Internal Medicine (Section on Pulmonary and Critical Care Medicine) [A. J. T., G-i. A., A. N. F., A. M. N., C. E. C., K. P. H., F. H. C.], Biochemistry [B. M. W.], Pathology [T. E. K., M. C. W.], and Physiology/Pharmacology [F. H. C.], Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157

Recent studies have demonstrated that arachidonic acid (AA) may serve as an important signal that blocks cell proliferation of certain neoplastic cells. The current study was conducted to determine whether disruption of AA homeostasis influences breast cancer cell proliferation and death. Initial experiments revealed that inhibition of AA remodeling through membrane phospholipids by inhibitors of the enzyme, coenzyme A-independent transacylase (CoA-IT), attenuates the proliferation of the estrogen receptor-negative, MDA-MB-231, and estrogen receptor-positive, MCF-7 breast cancer cell lines. This growth inhibition was accompanied by a marked accumulation of AA in both free fatty acid and triglyceride forms, a marker of intracellular AA stress within mammalian cells. Cell cycle synchronization experiments revealed that the CoA-IT inhibitor, SB-98625, blocked MDA-MB-231 cell replication in early to mid G₁ phase. Time-lapse video microscopy, used to observe the changes in cell morphology associated with apoptosis, indicated that SB-98625 treatment induced early rounding and occasional blebbing but not late apoptotic events, blistering, and lysis. The cyclooxygenase inhibitors, NS-398 and indomethacin, were found to be less potent blockers of cell proliferation and poor inducers of cellular AA accumulation than CoA-IT inhibitors in these breast cancer cell lines. Finally, AA provided exogenously blocked the proliferation of MCF-7 cells, and this effect could be attenuated in MCF-7 cells overexpressing the glutathione peroxidase gene, GSHPx-1. Taken together, these experiments suggest that disruption of AA remodeling in a manner that increases intracellular AA may represent a novel therapeutic strategy to reduce cancer cell proliferation and that an oxidized AA metabolite is likely to mediate this effect.

This article has been cited by other articles:

				M. C. Seeds, K. K. Peachman, D. L. Bowton, K. L. Sivertson, and F. H. Chilton Regulation of Arachidonate Remodeling Enzymes Impacts Eosinophil Survival during Allergic Asthma Am. J. Respir. Cell Mol. Biol., September 1, 2009; 41(3): 358 - 366. [Abstract] [Full Text] [PDF]

				A. M. Monjazeb, K. P. High, A. Connoy, L. S. Hart, C. Koumenis, and F. H. Chilton Arachidonic acid-induced gene expression in colon cancer cells Carcinogenesis, October 1, 2006; 27(10): 1950 - 1960. [Abstract] [Full Text] [PDF]

				A. M. Kleinfeld and C. Okada Free fatty acid release from human breast cancer tissue inhibits cytotoxic T-lymphocyte-mediated killing J. Lipid Res., September 1, 2005; 46(9): 1983 - 1990. [Abstract] [Full Text] [PDF]

				C. Rondanino, M.-T. Bousser, M. Monsigny, and A.-C. Roche Sugar-dependent nuclear import of glycosylated proteins in living cells Glycobiology, July 1, 2003; 13(7): 509 - 519. [Abstract] [Full Text] [PDF]

				C. E. Clay, A. Monjazeb, J. Thorburn, F. H. Chilton, and K. P. High 15-Deoxy-{Delta}12,14-prostaglandin J2-induced apoptosis does not require PPAR{gamma} in breast cancer cells J. Lipid Res., November 1, 2002; 43(11): 1818 - 1828. [Abstract] [Full Text] [PDF]

				C. E. Clay, G.-i. Atsumi, K. P. High, and F. H. Chilton Early de Novo Gene Expression Is Required for 15-Deoxy-Delta 12,14-prostaglandin J2-induced Apoptosis in Breast Cancer Cells J. Biol. Chem., December 7, 2001; 276(50): 47131 - 47135. [Abstract] [Full Text] [PDF]

				E. Boilard and M. E. Surette Anti-CD3 and Concanavalin A-induced Human T Cell Proliferation Is Associated with an Increased Rate of Arachidonate-Phospholipid Remodeling. LACK OF INVOLVEMENT OF GROUP IV AND GROUP VI PHOSPHOLIPASE A2 IN REMODELING AND INCREASED SUSCEPTIBILITY OF PROLIFERATING T CELLS TO CoA-INDEPENDENT TRANSACYLASE INHIBITOR-INDUCED APOPTOSIS J. Biol. Chem., May 11, 2001; 276(20): 17568 - 17575. [Abstract] [Full Text] [PDF]

				A. N. Fonteh, T. LaPorte, D. Swan, and M. A. McAlexander A Decrease in Remodeling Accounts for the Accumulation of Arachidonic Acid in Murine Mast Cells Undergoing Apoptosis J. Biol. Chem., January 5, 2001; 276(2): 1439 - 1449. [Abstract] [Full Text] [PDF]