Back to Search
Start Over
Role of OATP transporters in steroid uptake by prostate cancer cells in vivo
- Source :
- Prostate cancer and prostatic diseases
- Publication Year :
- 2016
- Publisher :
- Springer Science and Business Media LLC, 2016.
-
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.
- Subjects :
- Male
0301 basic medicine
Oncology
Cancer Research
Gene Expression
Organic Anion Transporters
Mice
Prostate cancer
0302 clinical medicine
Chlorocebus aethiops
DHEA-S
Testosterone
OATP
steroid uptake
biology
prostate cancer
castration resistant
3. Good health
Organic anion-transporting polypeptide
transporter
030220 oncology & carcinogenesis
COS Cells
Steroids
medicine.medical_specialty
medicine.drug_class
Urology
Dehydroepiandrosterone
Article
03 medical and health sciences
In vivo
Cell Line, Tumor
Internal medicine
LNCaP
medicine
Animals
Humans
xenograft
business.industry
Prostatic Neoplasms
Androgen
medicine.disease
Xenograft Model Antitumor Assays
Androgen receptor
Disease Models, Animal
030104 developmental biology
Endocrinology
SLCO
biology.protein
business
Subjects
Details
- ISSN :
- 14765608 and 13657852
- Volume :
- 20
- Database :
- OpenAIRE
- Journal :
- Prostate Cancer and Prostatic Diseases
- Accession number :
- edsair.doi.dedup.....7b25d9a4e7fda18c195a7a808bb03ee9