Vitamin D autocrine system and prostate cancer prevention and treatment

Cytochrome P450 (CYP) enzymes play crucial roles in vitamin D metabolism and actions, including hepatic vitamin D-25-hydroxylase and renal 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) for the synthesis of the active form 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), and 25-hydroxyvitamin D-24-hydroxylase (CYP24A1) also in the kidneys to inactive 1α,25(OH)2D3. The active hormone has high affinity for and interacts with vitamin D receptor (VDR), a transcription factor, to induce anti-proliferative, anti-invasive, anti-angiogenic, anti-inflammatory, pro-apoptotic and pro-differentiation actions in prostate cancer cells. However, it is now recognized that CYP27B1 and CYP24A1 are also expressed in many tissues and cells, including the prostate. Although six CYP enzymes have been identified with 25-hydroxylase activity, the two major ones are CYP27A1 and CYP2R1, and both are expressed in the prostate with CYP2R1 as the main 25-hydroxylase. The finding demonstrates that prostate tissue has the ability to activate and inactivate vitamin D in an autocrine/paracrine fashion. Recently 25-hydroxyvitamin D3 (25(OH)D3) and its analogs, without converting to their 1α-hydroxylated counter parts, have been shown to bind to VDR as agonists to modulate various gene expressions that ultimately lead to cell growth arrest and other anti-tumor activities. The finding suggests that the circulating levels of 25(OH)D, and the autocrine synthesis of 25(OH)D3 and 1α,25(OH)2D3 may play an important role in regulating the growth of prostate cancer. Thus, in addition to 1α,25(OH)2D3 analogs, the presence of CYP2R1, CYP27B1 and CYP24A1 in the prostate suggests that the analogs of vitamin D3 and 25(OH)D3, especially those that are resistant to CYP24A1 degradation, can be developed and used for the prevention and treatment of prostate cancer.