title: Differential Expression of OATP1B3 Mediates Unconjugated Testosterone Influx.
abstract: Castration-resistant prostate cancer (CRPC) has greater intratumoral testosterone concentrations than similar tumors from eugonadal men; simple diffusion does not account for this observation. This study was undertaken to ascertain the androgen uptake kinetics, functional, and clinical relevance ofde novoexpression of the steroid hormone transporter OATP1B3 (SLCO1B3). Experiments testing the cellular uptake of androgens suggest that testosterone is an excellent substrate of OATP1B3 (Km= 23.2 μmol/L;Vmax= 321.6 pmol/mg/minute), and cells expressing a doxycycline-inducibleSLCO1B3construct had greater uptake of a clinically relevant concentration of 3H-testosterone (50 nmol/L; 1.6-fold,P= 0.0027). When compared withSlco1b2(-/-) mice,Slco1b2(-/-)/hSLCO1B3knockins had greater hepatic uptake (15% greater AUC,P= 0.0040) and lower plasma exposure to 3H-testosterone (17% lower AUC,P= 0.0030). Of 82 transporters genes,SLCO1B3is the second-most differentially expressed transporter in CRPC cell lines (116-fold vs. androgen-sensitive cells), with a differentially spliced cancer-type ct-SLCO1B3making up the majority ofSLCO1B3expression. Overexpression ofSLCO1B3in androgen-responsive cells results in 1.5- to 2-fold greater testosterone uptake, whereas siRNA knockdown ofSLCO1B3in CRPC cells did not change intracellular testosterone concentration. Primary human prostate tumors expressSLCO1B3to a greater extent thanct-SLCO1B3(26% of totalSLCO1B3expression vs. 0.08%), suggesting that androgen uptake in these tumor cells also is greater. Non-liver tumors do not differentially express SLCO1B3.Implications:This study suggests thatde novoOATP1B3 expression in prostate cancer drives greater androgen uptake and is consistent with previous observations that greater OATP1B3 activity results in the development of androgen deprivation therapy resistance and shorter overall survival.Mol Cancer Res; 15(8); 1096-105. ©2017 AACR.
authors.affiliation: Clinical Pharmacology Program, Office of the Clinical Director, NCI, Bethesda, Maryland.
authors.forename: Tristan M
authors.initials: TM
authors.lastname: Sissung
authors.affiliation: Molecular Pharmacology Section, Genitourinary Malignancies Branch, NCI, Bethesda, Maryland.
authors.forename: Ariel M
authors.initials: AM
authors.lastname: Ley
authors.affiliation: Molecular Pharmacology Section, Genitourinary Malignancies Branch, NCI, Bethesda, Maryland.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Strope
authors.affiliation: Molecular Pharmacology Section, Genitourinary Malignancies Branch, NCI, Bethesda, Maryland.
authors.forename: Edel M
authors.initials: EM
authors.lastname: McCrea
authors.affiliation: Molecular Pharmacology Section, Genitourinary Malignancies Branch, NCI, Bethesda, Maryland.
authors.forename: Shaunna
authors.initials: S
authors.lastname: Beedie
authors.affiliation: Clinical Pharmacology Program, Office of the Clinical Director, NCI, Bethesda, Maryland.
authors.forename: Cody J
authors.initials: CJ
authors.lastname: Peer
authors.affiliation: Laboratory of Cell Biology, NCI, Bethesda, Maryland.
authors.forename: Suneet
authors.initials: S
authors.lastname: Shukla
authors.affiliation: Molecular Pharmacology Section, Genitourinary Malignancies Branch, NCI, Bethesda, Maryland.
authors.forename: Jennifer
authors.initials: J
authors.lastname: van Velkinburgh
authors.affiliation: Molecular Pharmacology Section, Genitourinary Malignancies Branch, NCI, Bethesda, Maryland.
authors.forename: Kelie
authors.initials: K
authors.lastname: Reece
authors.affiliation: Molecular Pharmacology Section, Genitourinary Malignancies Branch, NCI, Bethesda, Maryland.
authors.forename: Sarah
authors.initials: S
authors.lastname: Troutman
authors.affiliation: Molecular Pharmacology Section, Genitourinary Malignancies Branch, NCI, Bethesda, Maryland.
authors.forename: Tessa
authors.initials: T
authors.lastname: Campbell
authors.affiliation: Molecular Pharmacology Section, Genitourinary Malignancies Branch, NCI, Bethesda, Maryland.
authors.forename: Elena
authors.initials: E
authors.lastname: Fernandez
authors.affiliation: Molecular Pharmacology Section, Genitourinary Malignancies Branch, NCI, Bethesda, Maryland.
authors.forename: Phoebe
authors.initials: P
authors.lastname: Huang
authors.affiliation: Laboratory of Cancer Biology and Genetics, NCI, Bethesda, Maryland.
authors.forename: Jordan
authors.initials: J
authors.lastname: Smith
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky.
authors.forename: Nilay
authors.initials: N
authors.lastname: Thakkar
authors.affiliation: Biostatistics and Data Management Section, NCI, Bethesda, Maryland.
authors.forename: David J
authors.initials: DJ
authors.lastname: Venzon
authors.affiliation: Department of Clinical Pharmacy and Diagnostics, University of Vienna, Vienna, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Brenner
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Wooin
authors.initials: W
authors.lastname: Lee
authors.affiliation: Translational Surgical Pathology Section, NCI, Bethesda, Maryland.
authors.forename: Maria
authors.initials: M
authors.lastname: Merino
authors.affiliation: Laboratory of Cancer Biology and Genetics, NCI, Bethesda, Maryland.
authors.forename: Ji
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Clinical Pharmacy and Diagnostics, University of Vienna, Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Jager
authors.affiliation: Molecular Pharmacology Section, Genitourinary Malignancies Branch, NCI, Bethesda, Maryland.
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Price
authors.affiliation: Molecular Pharmacology Section, Genitourinary Malignancies Branch, NCI, Bethesda, Maryland.
authors.forename: Cindy H
authors.initials: CH
authors.lastname: Chau
authors.affiliation: Clinical Pharmacology Program, Office of the Clinical Director, NCI, Bethesda, Maryland. wf13e@nih.gov.|Molecular Pharmacology Section, Genitourinary Malignancies Branch, NCI, Bethesda, Maryland.
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
mesh_terms: D000728:Androgens / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D018345:Mice, Knockout; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3 / Q000235:genetics*; D013739:Testosterone / Q000008:administration & dosage / Q000378:metabolism*
chemical_list: D000728:Androgens; D034741:RNA, Small Interfering; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013739:Testosterone