Altered expression of cytochrome P450 enzymes involved in metabolism of androgens and vitamin D in the prostate as a risk factor for prostate cancer.

Abstract

Prostate cancer is the most common malignant disease among men. The signaling pathways, regulated by the androgen and vitamin D receptors, play a key role in prostate cancer. The intracellular level of androgens and vitamin D determines not only receptor functionality, but also the efficacy of cellular processes regulated by them (cell proliferation, apoptosis, differentiation etc.). It is known that several androgen-metabolizing P450s (CYP3A4/5/43 and CYP2B6) and P450 enzymes (CYP2R1, CYP27A1, CYP27B1, CYP24A1, CYP3A4, CYP2J2), which are necessary for vitamin D metabolism, are expressed in the prostate. It was shown that alterations in an expression pattern of the certain cytochrome P450s might lead to the development of castration-resistant cancer (CYP3A4, CYP2J2, CYP24A1), and to chemo-resistance (CYP3A4, CYP3A5, CYP2B6) and early mortality (CYP2B6, CYP27A1, CYP24A1). Moreover, steroidogenic CYPs (CYP17A1, CYP11A1) are not expressed in normal prostate tissue. Alterations in their expression levels in steroidogenic tissues are closely associated with carcinogenesis, and, most importantly, with the development of aggressive forms of prostate cancer. Hence, it is important, to study how expression of CYPs in the prostate might be regulated, to understand the mechanisms of disease development and to improve the effectiveness of therapy. Several CYPs (CYP3A43, CYP2B6, CYP27A1, CYP24A1) can be considered as prognostic and diagnostic markers of prostate cancer. To propose personalized treatment, individual differences in CYP expression should be taken into account.