Aberrant expression of cyclooxygenase 2 (COX2), the enzyme responsible for synthesizing prostaglandin E2 (PGE2), is one of the early events in colorectal cancer (CRC) development. Repression of COX2 results in the inhibition of prostaglandin synthesis which can delay colon tumorigenesis. It has been shown previously that in cancer cells 1α,25-dihydroxyvitamin D3 (1,25D3) downregulates the expression of COX2 and increasing that of the PGE2 catabolizing enzyme 15-prostaglandin-dehydrogenase (15-PGDH). Due to the differentiation-promoting, pro-apoptotic and anti-proliferative effects calcium and 1,25D3 have become factors of great interest for the chemoprevention of CRC.

In order to study the effect of calcium on the PGE2 pathway, we treated the colon cancer cell line Caco-2 with low calcium (0.025 mM) for 48 hours. This led to an increase in COX2 expression while decreasing that of 15-PGDH. Similar effect was seen in vivo: in mice low calcium (0.04%) diet elevated COX2 expression in the colon when compared with the control diet (0.5%). Interestingly, expression of the vitamin D catabolizing enzyme, CYP24A1 was also augmented, in parallel with an increase of crypt cell proliferation. However, expression of the 1,25D3 synthesizing CYP27B1 was not affected. These results suggested that low dietary calcium might reduce 1,25D3 levels in the colon, thereby lowering the impact of 1,25D3 on the COX2-PGE2 pathway. To investigate whether this expression profile is prevalent also in the human colon, we screened over 200 tissue specimens from CRC patients by QRT-PCR. In colon tumors, the mRNA ratio of 15-PGDH and COX2 was significantly downregulated (p<0.0001). This unbalance implicates an elevated PGE2 production. In these tumor samples the CYP24A1/CYP27B1 mRNA ratio was also significantly increased (p<0.05) as compared with the adjacent mucosa. Additionally, CYP24A1 staining confirmed elevated levels of the enzyme in adenocarcinomas.

Thus, in these colorectal tumors local 1,25D3 levels were most probably insufficient to inhibit PGE2 accumulation due to high CYP24A1 expression. Low dietary calcium is a promoter of CYP24A1 expression. Our data represent one of the possible molecular mechanisms for the synergistic action of calcium and vitamin D levels in CRC chemoprevention.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1874.