Inhibition of 11β–hydroxysteroid dehydrogenase type II selectively blocks the tumor COX-2 pathway and suppresses colon carcinogenesis in mice and humans

Abstract

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 11β-hydroxysteroid dehydrogenase type II (11βHSD2), 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 11βHSD2 inhibited COX-2-mediated PGE 2 production in tumors and prevented adenoma formation, tumor growth, and metastasis in mice. Inhibition of 11βHSD2 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, 11βHSD2 inhibition represents what we believe to be a novel approach for CRC chemoprevention and therapy by increasing tumor glucocorticoid activity, which in turn selectively blocks local COX-2 activity.

Foxm1 Expression in Prostate Epithelial Cells Is Essential for Prostate Carcinogenesis

“…siRNA-mediated depletion of Foxm1 caused a significant reduction in Vegf-a mRNA in cultured TRAMP C2 mouse prostate adenocarcinoma cells in vitro (Fig. 4C), a finding consistent with regulation of Vegf-a by Foxm1 in pancreatic tumor cells (42 (43)(44)(45) were all decreased, whereas Hif-1a, Spdef, and Foxf1 mRNA levels did not change (Fig. 5A).…”

Staying a Step Ahead of Cancer

“…Abundance of COX-2 has been linked to the growth and proliferation of cancerous and pre-cancerous cells (Cesario et al 2011, Khan et al 2011. Inhibiting the COX pathways can alter cancerous and precancerous cells by decreasing angiogenesis and cell growth (Banu et al 2007, Half, Sun and Sinicrope 2007, Ishizaki et al 2006, Sheng et al 1997, Suh et al 2009, Tuynman et al 2008, Zhang et al 2009). In addition, COX inhibition enhances apoptosis and enables the immune system to recognize and target the cells for destruction (Hida et al 2000, Ding, Tong and Adrian 2000, Hsu et al 2000, Souza et al 2000.…”

11β-hydroxysteroid dehydrogenase type II: a Potential target for prevention of colonic tumorigenesis

“…The mechanism underlying increases in COX-2 expression in CRC is not completely understood. Recent studies have found that 11ßHSD2 mRNA levels are significantly higher in both human colonic small and large adenomas compared to adjacent normal colon tissues [40]. Immunohistochemical staining showed that increased 11ßHSD2 expression is primarily localized to adenoma epithelia and co-localized with increased COX-2 expression in human colonic adenomas.…”

“…Long-term excessive ingestion of licorice has been reported to induce hypokalemia and elevation of blood pressure in a subset of people [66]. Although these side effects were not seen in animal experiments, studies did observe that the concentrations of glycyrrhizic acid increased levels of active glucocorticoid levels in the kidney [40]. Although 11βHSD2 inhibition may result in salt-dependent hypertension due to activation of mineralocorticoid receptor by glucocorticoids in kidney, development of locally acting enteric 11ßHSD2 inhibitors that are not systemically absorbed would be a potential therapeutic means to prevent tumorigenesis [67].…”

“…Both 11ßHSD2 and COX-2 expression also increase in adenomas of Apc+/min mice. Mouse adenocarcinoma CT26 cells demonstrate significant tumorigenic activity and express high levels of COX-2, and both their proliferation in vitro and the size and number of CT26 tumors in vivo are sensitive to COX-2 inhibition [40]. CT26 cells also express 11ßHSD2.…”