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.
Highlights
Androgen depletion therapy (ADT) is the standard first line treatment in advanced prostate cancer [1]
We have previously shown that CYP3A5 is expressed in androgen receptor positive prostate cancer cell lines (LNCaP, C4-2 and 22RV1) and promotes activation of AR and prostate cancer growth [10]
Genotyping revealed that all the Non Hispanic White Americans (NHWA) lines carry the *3/*3 CYP3A5 variant in homozygous form
Summary
Androgen depletion therapy (ADT) is the standard first line treatment in advanced prostate cancer [1]. Throughout the entire natural history of prostate cancer, AR remains active and is still expressed in patients undergoing ADT [2,3,4]. Mutated AR often can bypass the need for androgen activation, and can act as transcriptional activator in the absence of androgens, promoting tumor growth [5]. Several new therapeutic approaches are available to AR signaling, one of them being blocking non-gonadal androgen synthesis [6]. Eventually the AR bypasses these strategies, leading to CRPC. Identification of novel mechanisms to block AR nuclear translocation represents an unmet need [7,8,9]
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