Altered expression of the vitamin D metabolizing enzymes CYP27B1 and CYP24A1 under the context of prostate aging and...

Low circulating levels of vitamin D are common at older ages and have been linked to an increased risk of prostate disease, including cancer. However, it has not yet been determined whether aging affects the ability of prostate cells to locally metabolize vitamin D into its active metabolite calcitriol and thus mediate the vitamin D signaling in autocrine and paracrine ways. By using a suitable rat model to interrogate spontaneous prostatic modifications over the course of aging, here we showed that both CYP27B1 and CYP24A1 enzymes, which are key players respectively involved with calcitriol synthesis and deactivation, were highly expressed in the prostate epithelium. Furthermore, as the animals aged, a drastic reduction of CYP27B1 levels was detected in total protein extracts and especially in epithelial areas of lesions, including tumors. On the other hand, CYP24A1 expression significantly increased with aging and remained elevated even in altered epithelia. Such intricate unbalance in regard to vitamin D metabolizing enzymes was strongly associated with reduced bioavailability of calcitriol in the senile prostate, which in addition to decreased expression of the vitamin D receptor, further limits the protective actions mediated by vitamin D signaling. This evidence was corroborated by the increased proliferative activity exactly at sites of lesions where the factors implicated with calcitriol synthesis and responsiveness had its expression inhibited. Taken together, our results emphasize a set of modifications over the course of aging with a high potential to hamper vitamin D signaling on the prostate. These findings highlight a crosstalk between vitamin D, aging, and prostate carcinogenesis, offering new potential targets in the prevention of malignancies and other aging-related disorders arising in the gland.