Abstract
Colorectal cancer is a leading cause of cancer deaths. The renin-angiotensin system (RAS) is upregulated in colorectal cancer, and epidemiologic studies suggest RAS inhibitors reduce cancer risk. Because Vitamin D (VD) receptor negatively regulates renin, we examined anticancer efficacy of VD and losartan (L), an angiotensin receptor blocker. Control Apc+/LoxP mice and tumor-forming Apc+/LoxP Cdx2P-Cre mice were randomized to unsupplemented Western diet (UN), or diets supplemented with VD, L, or VD+L, the latter to assess additive or synergistic effects. At 6months, mice were killed. Plasma Ca2+, 25(OH)D3, 1a, 25(OH) 2D3, renin, and angiotensin II (Ang II) were quantified. Colonic transcripts were assessed by qPCR and proteins by immunostaining and blotting. Cancer incidence and tumor burden were significantly lower in Cre+ VD and Cre+ L, but not in the Cre+ VD+L group. In Apc+/LoxP mice, VD increased plasma 1,25 (OH)2D3 and colonic VDR. In Apc+/LoxP-Cdx2P-Cre mice, plasma renin and Ang II, and colonic tumor AT1, AT2, and Cyp27B1 were increased and VDR downregulated. L increased, whereas VD decreased plasma renin and Ang II in Cre+ mice. VD or L inhibited tumor development, while exerting differential effects on plasma VD metabolites and RAS components. We speculate that AT1 is critical for tumor development, whereas RAS suppression plays a key role in VD chemoprevention. When combined with L, VD no longer increases active VD and colonic VDR in Cremice nor suppresses renin and Ang II in Cre+ mice, likely contributing to lack of chemopreventive efficacy of the combination.
Original language | English (US) |
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Pages (from-to) | 433-448 |
Number of pages | 16 |
Journal | Cancer Prevention Research |
Volume | 12 |
Issue number | 7 |
DOIs | |
State | Published - 2019 |
Funding
This work was supported by the NIH Grants (R01 CA164124 to M. Bissonnette; R01 CA180087-01 to Y.C. Li; and R01 CA171785-01A1 to J.S. Souris); P30DK42086 (Digestive Disease Research Core Center); and Samuel Freedman GI Cancer Laboratory Fund at University of Chicago and the University of Chicago Cancer Research Foundation (UCCRF) Women's Board.
ASJC Scopus subject areas
- Oncology
- Cancer Research