Role of CYP3A5 in Modulating Androgen Receptor Signaling and Its Relevance to African American Men with Prostate Cancer

Abstract

Androgen receptor signaling is crucial for prostate cancer growth and is positively regulated in part by intratumoral CYP3A5. As African American (AA) men often carry the wild type CYP3A5 and express high levels of CYP3A5 protein, we blocked the wild type CYP3A5 in AA origin prostate cancer cells and tested its effect on androgen receptor signaling. q-PCR based profiler assay identified several AR regulated genes known to regulate AR nuclear translocation, cell cycle progression, and cell growth. CYP3A5 processes several commonly prescribed drugs and many of these are CYP3A5 inducers or inhibitors. In this study, we test the effect of these commonly prescribed CYP3A5 inducers/inhibitors on AR signaling. The results show that the CYP3A5 inducers promoted AR nuclear translocation, downstream signaling, and cell growth, whereas CYP3A5 inhibitors abrogated them. The observed changes in AR activity is specific to alterations in CYP3A5 activity as the effects are reduced in the CYP3A5 knockout background. Both the inducers tested demonstrated increased cell growth of prostate cancer cells, whereas the inhibitors showed reduced cell growth. Further, characterization and utilization of the observation that CYP3A5 inducers and inhibitors alter AR signaling may provide guidance to physicians prescribing CYP3A5 modulating drugs to treat comorbidities in elderly patients undergoing ADT, particularly AA.

Comprehensive analysis of alternative splicing across multiple transcriptomic cohorts reveals prognostic signatures in prostate cancer

“…Genetic variation in CYP3A5 impacts drug response, which will affect individual response to therapeutic drugs. CYP3A5 inhibitors can enhance androgen depletion therapy (ADT), while inducers may reduce efficacy [61]; and its polymorphism may specifically decrease the risk of developing low-grade or early stage PCa in the Japanese population [62]. CYP4F12 encodes cytochrome p450 4F12 and an intron retention event in the CYP4F12 gene, has been previously demonstrated to hold prognostic value in cervical cancer, being incorporated into a retained intron-based signature model to predict overall survival in patients with cervical cancer [63].…”

Differential drug response in pulmonary arterial hypertension: The potential for precision medicine

“…The CYP3A5 allelic distribution may also provide a genetic link to potential racial disparities in PDE5 inhibitor response. CYP3A5*3 allele frequency varies from approximately 50% in African Americans, 70% in Chinese, to 90% in Caucasians 71,72 . The CYP3A5*1 allele is found in up to 15% of Caucasians, 60%–90% of African descent, and 23%–40% of Asians 73 .…”

“…CYP3A5*3 allele frequency varies from approximately 50% in African Americans, 70% in Chinese, to 90% in Caucasians. 71 , 72 The CYP3A5*1 allele is found in up to 15% of Caucasians, 60%–90% of African descent, and 23%–40% of Asians. 73 In addition to CYP3A5, the CYP3A4*22 (rs35599367) variant may also be associated with peak plasma concentrations of sildenafil, but this only reached significance in a white population.…”

The Role of CYP3A in Health and Disease

“…Intratumoral activation of CYP3A5 in prostate cancer is reported to mediate the growth of prostate cancer cells by facilitating nuclear translocation of AR [ 442 ]. The observed influence on AR signaling is due to the change in CYP3A5 activity, not in CYP3A4 activity [ 443 ].…”

“…Proof that CYP3A5 inducers promote AR nuclear translocation, downstream signaling, and cell growth whereas CYP3A5 inhibitors reverse these actions is also offered by a study on African Americans, who often carry wild-type CYP3A5 and overexpress the CYP3A5 protein. The observed alterations of AR activity turned out to be specific to changes in CYP3A5 activity because the effects were attenuated by a CYP3A5 knockout in MDAPCa2b cells [ 443 ].…”