© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 14, 1136-1142,
July 19, 2000
© 2000 Oxford University Press
ACCELERATED DISCOVERY |
15-LOX-1: a Novel Molecular Target of Nonsteroidal Anti-inflammatory Drug-Induced Apoptosis in Colorectal Cancer Cells
Affiliations of authors: I. Shureiqi (Departments of Clinical Cancer Prevention and Gastrointestinal Medical Oncology and Digestive Diseases), D. Chen, S. M. Lippman (Department of Clinical Cancer Prevention), J. Jack Lee (Department of Biostatistics), P. Yang, R. A. Newman (Department of Experimental Therapeutics), R. Lotan (Division of Cancer Prevention), S. M. Fischer (Department of Carcinogenesis), The University of Texas M. D. Anderson Cancer Center, Houston; D. E. Brenner, Division of Hematology and Oncology, Departments of Internal Medicine and Pharmacology, University of Michigan Medical School, Ann Arbor.
Correspondence to: Scott M. Lippman, M.D., Department of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 236, Houston, TX 77030-4095 (e-mail: slippman{at}mdanderson.org).
Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) appear to act via induction of apoptosis—programmed cell death—as potential colorectal cancer chemopreventive agents. NSAIDs can alter the production of different metabolites of polyunsaturated fatty acids (linoleic and arachidonic acids) through effects on lipoxygenases (LOXs) and cyclooxygenases. 15-LOX-1 is the main enzyme for metabolizing colonic linoleic acid to 13-S-hydroxyoctadecadienoic acid (13-S-HODE), which induces apoptosis. In human colorectal cancers, the expression of this enzyme is reduced. NSAIDs can increase 15-LOX enzymatic activity in normal leukocytes, but their effects on 15-LOX in neoplastic cells have been unknown. We tested the hypothesis that NSAIDs induce apoptosis in colorectal cancer cells by increasing the protein expression and enzymatic activity of 15-LOX-1. Methods: We assessed 15-LOX-1 protein expression and enzymatic activity, 13-S-HODE levels, and 15-LOX-1 inhibition in association with cellular growth inhibition and apoptosis induced by NSAIDs (primarily sulindac and NS-398) in two colorectal cancer cell lines (RKO and HT-29). All P values are two-sided. Results: Sulindac and NS-398 progressively increased 15-LOX-1 protein expression in RKO cells (at 24, 48, and 72 hours) in association with subsequent growth inhibition and apoptosis. Increased 13-S-HODE levels and the formation of 15-hydroxyeicosatetraenoic acid on incubation of the cells with the substrate arachidonic acid confirmed the enzymatic activity of 15-LOX-1. Inhibition of 15-LOX-1 in RKO cells by treatment with caffeic acid blocked NS-398-induced 13-S-HODE production, cellular growth inhibition, and apoptosis (P = .007, P<.0001, and P<.0001, respectively); growth inhibition and apoptosis were restored by adding exogenous 13-S-HODE (P<.0001 for each) but not its parent compound, linoleic acid (P = 1.0 for each). Similar results occurred with other NSAIDs and in HT-29 cells. Conclusions: These data identify 15-LOX-1 as a novel molecular target of NSAIDs for inducing apoptosis in colorectal carcinogenesis.
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