Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 119, Issue 4, Pages 876-885Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI37398
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Funding
- American Cancer Society [ACS-IRG-58-009-47]
- NIH [DK39261, DK62794, CA94849, DK74359, DK48831, CA97386]
- Department of Veterans Affairs
- NATIONAL CANCER INSTITUTE [R01CA097386, R01CA094849] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P50DK039261, R01DK062794, R01DK074359, R01DK048831] Funding Source: NIH RePORTER
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Colorectal cancer (CRC) is a leading cause of cancer death, yet primary prevention remains the best approach to reducing overall morbidity and mortality. Studies have shown that COX-2-derived PGE(2) promotes CRC progression, and both nonselective COX inhibitors (NSAIDs) and selective COX-2 inhibitors (such as glucocorticoids) reduce the number and size of colonic adenomas. However, increased gastrointestinal side effects of NSAIDs and increased cardiovascular risks of selective COX-2 inhibitors limit their use in chemoprevention of CRC. We found that expression of 11 beta-hydroxysteroid dehydrogenase type II (11 beta HSD2), which converts active glucocorticoids to inactive keto-forms, increased in human colonic and Apc(+/min) mouse intestinal adenomas and correlated with increased COX-2 expression and activity. Furthermore, pharmacologic inhibition or gene silencing of 11 beta HSD2 inhibited COX-2-mediated PGE(2) production in tumors and prevented adenoma formation, tumor growth, and metastasis in mice. Inhibition of 11 beta HSD2 did not reduce systemic prostacyclin production or accelerate atherosclerosis in mice, thereby avoiding the major cardiovascular side effects seen with systemic COX-2 inhibitors. Therefore, 11 beta HSD2 inhibition represents what we believe to be a novel approach for CRC chemoprevention and therapy by increasing tumor glucocorticoid. activity, which in rum selectively blocks local COX-2 activity.
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