title: Role of OATP transporters in steroid uptake by prostate cancer cells in vivo.
abstract: Epidemiologic and in vitro studies suggest that SLCO-encoded organic anion transporting polypeptide (OATP) transporters influence the response of prostate cancer (PCa) to androgen deprivation by altering intratumor androgens. We have previously shown that castration-resistant metastases express multiple SLCO transporters at significantly higher levels than primary PCa, suggesting that 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.
  
  
  
  We sought to determine whether OATP-mediated steroid transport can measurably alter PCa androgen levels in vivo. We evaluated the uptake of dehydroepiandrosterone (DHEAS), E1S and testosterone in LNCaP cells engineered to express OATP1B1, 1B3, 2B1 or 4A1. We measured the 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 intratumor accumulation of administered steroids by mass spectrometry.
  
  
  
  OATP1B1- and 2B-expressing xenografts each showed a threefold 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 (~15 μg dl-1), 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 the substantial circulating testosterone levels found in eugonadal men, a consistent effect of OATP1B1, 2B1 or 4A1 on testosterone uptake in vivo was not detected.
  
  
  
  OATP transporters measurably alter DHEAS uptake and intratumor 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 androgen receptor signaling in PCa tumors, and support prospective evaluation of studies designed to test inhibition of OATP-mediated DHEAS uptake and utilization.
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Green
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kaipainen
authors.affiliation: Research and Development - Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Bullock
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Lucas
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Matson
authors.affiliation: Research and Development - Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA.
authors.forename: W A
authors.initials: WA
authors.lastname: Banks
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Mostaghel
mesh_terms: D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D008297:Male; D051379:Mice; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013256:Steroids / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D027361:Organic Anion Transporters; D013256:Steroids