Role of OATP transporters in steroid uptake by prostate cancer cells in vivo.

Abstract

BackgroundEpidemiologic and in vitro studies suggest SLCO-encoded OATP transporters influence the response of prostate cancer (PCa) to androgen deprivation by altering intra-tumor androgens. We have previously shown that castration resistant metastases express multiple SLCO transporters at significantly higher levels than primary PCa, suggesting OATP-mediated steroid transport is biologically relevant in advanced disease. However, whether OATP-mediated steroid transport can actually modify prostate tumor androgen levels in vivo has never been demonstrated.MethodsWe sought to determine whether OATP-mediated steroid transport can measurably alter PCa androgen levels in vivo. We evaluated uptake of DHEAS, E1S and testosterone in LNCaP cells engineered to express OATP1B1, 1B3, 2B1 or 4A1. We measured uptake via administration of tritiated steroids to castrate mice bearing vector control or OATP1B1, 2B1 or 4A1-expressing xenografts. We treated tumor-bearing mice with DHEAS and testosterone at physiologically relevant levels and measured intra-tumor accumulation of administered steroids by mass spectrometry.ResultsOATP1B1 and 2B-expressing xenografts each showed a 3-fold increase in tritiated-DHEAS uptake vs vector controls (p=0.002 and p=0.036, respectively). At circulating DHEAS levels similar to those in abiraterone-treated men (~15ug/dL) OATP1B1 and 2B1-expressing xenografts showed a 3.9-fold (p=0.057) and 1.9-fold (p=0.048) increase in tumor accumulation of DHEAS, and a 1.6-fold (p=0.057) and 2.7-fold (p=0.095) increase in DHEA, respectively. At testosterone levels found in eugonadal men, a consistent effect of OATP1B1, 2B1 or 4A1 on testosterone uptake in vivo was not detected.ConclusionsOATP transporters measurably alter DHEAS uptake and intra-tumor androgen levels in prostate tumors in vivo, even at circulating androgen levels achieved in abiraterone-treated patients. These novel data emphasize the continued need to inhibit ligand-mediated AR signaling in PCa tumors, and support prospective evaluation of studies designed to test inhibition of OATP-mediated DHEAS uptake and utilization.