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Inhibition of 11beta-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 PGE2 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 11beta-hydroxysteroid dehydrogenase type II (11betaHSD2), 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 11betaHSD2 inhibited COX-2-mediated PGE2 production in tumors and prevented adenoma formation, tumor growth, and metastasis in mice. Inhibition of 11betaHSD2 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, 11betaHSD2 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.

SUBMITTER: Zhang MZ

PROVIDER: S-EPMC2662561 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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

Zhang Ming-Zhi MZ Xu Jie J Yao Bing B Yin Huiyong H Cai Qiuyin Q Shrubsole Martha J MJ Chen Xiwu X Kon Valentina V Zheng Wei W Pozzi Ambra A Harris Raymond C RC

The Journal of clinical investigation 20090323 4

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 PGE2 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 li ...[more]

PMID: 19307727

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Project description:BACKGROUND: Leydig cells are the primary source of testosterone in male vertebrates. The biosynthesis of testosterone in Leydig cells is strictly dependent on luteinizing hormone (LH). On the other hand, it can be directly inhibited by excessive glucocorticoid (Corticosterone, CORT, in rats) which is beyond the protective capability of 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) and type 2 (11beta-HSD2; encoded by gene Hsd11b2 in rats) in Leydig cells. Our previous study found that LH increases 11beta-HSD1 expression in rat Leydig cells, but the effect of LH on the expression and activity of 11beta-HSD2 is not investigated yet. METHODS: The Leydig cells were isolated from male Sprague-Dawley rats (90 days of age). After Leydig cells were incubated either for 24 h with various concentrations of LH (2.5, 5, 10 and 20 ng/mL) or for different time periods (2, 8, 12 and 24 h) with 20 ng/mL LH, the mRNA expression of 11beta-HSD2 was measured by real-time PCR. 11beta-HSD2 protein levels in Leydig cells were assayed by Western Blot and 11beta-HSD2 enzyme activity was determined by calculating the ratio of conversion of [3H]CORT to [3H]11-dehydrocorticosterone by 24 h after stimulation with 20 ng/ml LH. Four reporter gene plasmids containing various lengths of Hsd11b2 promoter region were constructed and transfected into mouse Leydig tumor cells to investigate the effect of LH on Hsd11b2 transcription. A glucocorticoid-responsive reporter gene plasmid, GRE-Luc, was constructed. To evaluate influence of LH on intracellular glucocorticoid level, rat Leydig cells were transfected with GRE-Luc, and luciferase activities were measured after incubation with CORT alone or CORT plus LH. RESULTS: We observed dose- and temporal-dependent induction of rat 11beta-HSD2 mRNA expression in Leydig cells subject to LH stimulation. The protein and enzyme activity of 11beta-HSD2 and the luciferase activity of reporter gene driven by promoter regions of Hsd11b2 were increased by LH treatment. LH decreased the glucocorticoid-induced luciferase activity of GRE-Luc reporter gene. CONCLUSION: The results of the present study suggest that LH increases the expression and enzyme activity of 11beta-HSD2, and therefore enhances capacity for oxidative inactivation of glucocorticoid in rat Leydig cells in vitro.

Project description:INTRODUCTION: The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes the conversion of the hormonally inactive cortisone to active cortisol, thus facilitating glucocorticoid receptor activation in target tissues. Increased expression of 11beta-HSD1 in adipose tissue has been associated with obesity and insulin resistance. In this study, we investigated the association of two 11beta-HSD1 gene (HSD11B1) polymorphisms with the metabolic syndrome (MetS) and its characteristics in the Bosnian population. MATERIALS AND METHODS: The study included 86 participants: 43 patients diagnosed with MetS and 43 healthy controls. Subjects were genotyped for two HSD11B1 gene polymorphisms: rs846910: G > A and rs45487298: insA, by the high resolution melting curve analysis. Genotype distribution and an influence of genotypes on clinical and biochemical parameters were assessed. RESULTS: There was no significant difference in the mutated allele frequencies for the two HSD11B1 gene polymorphisms between MetS patients and controls. In MetS patients, no significant associations between disease-associated traits and rs45487298: insA were found. Regarding rs846910: G > Avariant, heterozygous patients (G/A) had significantly lower systolic (P = 0.017) and diastolic blood pressure (P = 0.015), lower HOMA-IR index (P = 0.011) and higher LDL-cholesterol levels (P = 0.049), compared to the wild-type homozygotes. In the control group, rs45487298: insA polymorphism was associated with lower fasting plasma insulin levels (P = 0.041), lower homeostasis model assessment insulin resistance (HOMA-IR) index (P = 0.041) and lower diastolic blood pressure (P = 0.048). Significant differences between rs846910: G > A genotypes in controls were not detected. Haplotype analysis confirmed the association of rs45487298: insA with markers of insulin resistance in the control subjects. CONCLUSIONS: Our results indicate that a common rs45487298: insA polymorphism in HSD1181 gene may have a protective effect against insulin resistance.

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Dataset Information

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

Publications

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

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