Molecular interaction between vitamin D signaling and colon carcinogenesis
Abstract
High vitamin D status, measured by serum level of 25-hydroxyvitamin D (25(OH)D), has been proposed as protective against colorectal cancer. The anti-cancer effects of vitamin D are mediated through the active form of the hormone 1,25 dihydroxyvitamin D (1,25(OH)2D), a ligand for activation of the vitamin D receptor (VDR). Recently in vitro studies using colon cancer models suggest that ligand-activated VDR can suppress β-catenin transcriptional activity. β-catenin is a transcription factor that regulates genes whose protein products promote proliferation and β-catenin activity is increased in 70% of colorectal cancers due to adenomatous polyposis coli (APC) inactivating gene mutations. Thus activating vitamin D signaling through the VDR may decrease proliferation during colon carcinogenesis by antagonizing β-catenin function. To test this hypothesis in vivo, mice with high colonic β-catenin signaling (CAC; APCΔ580/Δ580) were given an intraperitoneal (i.p.) injection of 25(OH)D or 1,25(OH) 2D to activate the VDR. However, these treatments had no effect on β-catenin signaling and proliferationin vivo. We found that VDR expression was lowered in mice with high colonic β-catenin signaling, suggesting that cancerous events may suppress VDR action. Next we examined mechanisms for suppression of vitamin D signaling. We found that prolonged MAPK activation induced by arsenic trioxide significantly decreased VDR levels and 1,25(OH) 2D-induced gene expression in proliferating Caco-2 cells. In human colon cancer prolonged MAPK activation can result from KRAS activating mutations that are seen in 40% of human colon cancers. We tested the impact of constitutively active RAS signaling on vitamin D transcriptional action and found that it decreased 1,25(OH)2D-mediated transcriptional activity and reduced VDR level in intestinal epithelial cells. VDR gene transcription is controlled by multiple regulatory regions and access to three of these was suppressed in cells with activation of RAS. Collectively our data demonstrates that common molecular events typically seen in human colon cancer (i.e. APC inactivating and KRAS activating mutations) suppress VDR expression and this may impair the chemopreventative effects of vitamin D.
Degree
Ph.D.
Advisors
Fleet, Purdue University.
Subject Area
Molecular biology|Oncology
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