Is the vitamin D catabolising enzyme CYP24A1 an oncogene?

Epidemiological studies have shown that high serum levels of 25-hydroxyvitamin D3 , the precursor of the active vitamin D metabolite, correlate with low incidence of colon cancer. Since the synthesizing and catabolic vitamin D hydroxylases are active also in colonocytes, colonic synthesis of the antimitotic, prodifferentiating active vitamin D metabolite, 1,25-(OH)2 -D3 , in sufficient amounts could prevent tumour progression and high serum precursor levels could support this synthesis. CYP24A1 seems to be an oncogene that, through as yet not well understood mechanisms, becomes amplified or up-regulated in several malignancies, participating in the onset and development of tumours. We hypothesize that unbalanced high expression of CYP24A1 may result in local deficiencies of active vitamin D, restraining its regulatory functions. Therefore suppression of CYP24A1 should restore and potentiate the anti-tumour effects of 1,25-(OH)2 -D3 . The main focus of this study is to elucidate the role of CYP24A1 in disruption of the anti-tumourigenic action of the active vitamin D in the colon. We expect to identify the mechanisms causing unbalanced expression of this enzyme and to find remedies that would restore normal vitamin D signalling. Our study will clarify whether unbalanced colonic overexpression of CYP24A1 always results in impaired vitamin D signalling and whether CYP24A1 suppression in vivo would restore or enhance the anti-proliferative, pro- apoptotic, anti-tumourigenic effect of 1,25-(OH)2 -D3 thus providing unequivocal evidence whether CYP24A1 is an attractive and promising target for chemopreventive and therapeutic strategies. First we propose to explore genetic and epigenetic causes of CYP24A1 overexpression in colon cancer cell lines and colorectal tumours. We will evaluate if there is a correlation between CYP24A1 expression, tissue 1,25-(OH)2 - D3 concentration, and vitamin D signalling in colon cancer cell lines and colorectal tumours. Then we will examine the effectiveness of CYP24A1 suppression on vitamin D signalling in two mouse models, one with colon-specific cyp24a1 null mutation the other with colon-specific overexpression. We will evaluate the effect of lack or overexpression of colonic cyp24a1 on carcinogen-induced colon tumour formation in mice. There exists enough evidence that the vitamin D system becomes compromised during cancer progression, be it in the colon, breast or prostate. Thus elucidation of mechanisms through which local availability of 1,25-(OH)2 -D3 could be enhanced is of prime relevance for the design of chemoprevention protocols.

Epidemiological studies have shown that vitamin D insufficiency correlates with increased incidence of cancer of the large bowel. Vitamin D has cancer preventive effects in several organs, such as the colon (large bowel), breast or prostate. We were able to show with this project that high vitamin D intake prevented the formation of cancer in mice that were treated with substances that normally cause cancer. The enzyme 1,25 dihydroxyvitamin D 24 hydroxylase (24OHase) is a molecule that degrades vitamin D. In several tumours this molecule is present in much higher concentrations than in the corresponding normal tissue. Thus in these tumours vitamin D is probably much quicker degraded and cannot exert its anti-cancer action. We discovered that high levels of 24OHase in colonic tumours are caused by an increase in the number of the gene that is coding for this molecule. In some of the colon cancer cells there are more than the usual two copies of this gene. The tumours that have high levels of 24OHase grow much faster than tumours that have normal amount of this enzyme. In these tumours vitamin D has no anti-cancer effect anymore. Our results suggest that vitamin D is probably more effective in preventing cancer, and less effective in patients with high levels of the degrading enzyme in their tumours.