Working Paper Article Version 1 This version is not peer-reviewed

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

Version 1 : Received: 5 March 2020 / Approved: 6 March 2020 / Online: 6 March 2020 (03:33:52 CET)

A peer-reviewed article of this Preprint also exists.

Gorjala, P.; Kittles, R.A.; Goodman, O.B., Jr.; Mitra, R. Role of CYP3A5 in Modulating Androgen Receptor Signaling and Its Relevance to African American Men with Prostate Cancer. Cancers 2020, 12, 989. Gorjala, P.; Kittles, R.A.; Goodman, O.B., Jr.; Mitra, R. Role of CYP3A5 in Modulating Androgen Receptor Signaling and Its Relevance to African American Men with Prostate Cancer. Cancers 2020, 12, 989.

Journal reference: Cancers 2020, 12, 989
DOI: 10.3390/cancers12040989

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 level 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. 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.

Subject Areas

CYP3A5; androgen receptor; African American; CYP3A5 inhibitors/inducers

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