title: The Efflux Transporter ABCG2 Maintains Prostate Stem Cells.
abstract: Prostate stem cells (PSC) are characterized by their intrinsic resistance to androgen deprivation therapy (ADT), possibly due to the lack of androgen receptor (AR) expression. PSCs resistance to ADT and PSC expansion in castration resistant prostate cancer (CRPC) has sparked great interest in using differentiation therapy as an adjuvant to ADT. Understanding the mechanisms, by which PSCs maintain their undifferentiated phenotype, thus has important implications in differentiation therapy. In the prostate, the ATP binding cassette sub-family G member 2 (ABCG2) transporters, which enrich for AR-positive, ADT-resistant PSCs, play an important role in regulating the intracellular androgen levels by effluxing androgens. We hypothesized that the ABCG2-mediated androgen efflux is responsible for maintaining PSCs in an undifferentiated state. Using the HPr-1-AR (nontumorigenic) and CWR-R1 (tumorigenic) prostate cell lines, it was demonstrated that inhibiting the ABCG2-mediated androgen efflux, with Ko143 (ABCG2 inhibitor), increased the nuclear AR expression due to elevated intracellular androgen levels. Increased nuclear translocation of AR is followed by increased expression of AR regulated genes, a delayed cell growth response, and increased luminal differentiation. Furthermore, Ko143 reduced tumor growth rates in mice implanted with ABCG2-expressing CWR-R1 cells. In addition, Ko143-treated mice had more differentiated tumors as evidenced by an increased percentage of CK8+/AR+luminal cells and decreased percentage of ABCG2-expressing cells. Thus, inhibiting ABCG2-mediated androgen efflux forces the PSCs to undergo an AR-modulated differentiation to an ADT-sensitive luminal phenotype.
  
  
  
  This study identifies the mechanism by which the prostate stem cell marker, ABCG2, plays a role in prostate stem cell maintenance and provides a rationale for targeting ABCG2 for differentiation therapy in prostate cancer. Mol Cancer Res; 15(2); 128-40. ©2016 AACR.
authors.affiliation: Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Neha G
authors.initials: NG
authors.lastname: Sabnis
authors.affiliation: Department of Bioinformatics & Biostatistics, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Austin
authors.initials: A
authors.lastname: Miller
authors.affiliation: Department of Genitourinary Medical Oncology - Research, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Titus
authors.affiliation: Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute, Buffalo, New York. Wendy.Huss@RoswellPark.org.|Department of Urologic Oncology, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Huss
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000728:Androgens / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D054659:Diketopiperazines / Q000494:pharmacology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism; D013739:Testosterone / Q000097:blood
chemical_list: C541506:3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino(1',2'-1,6)pyrido(3,4-b)indol-3-yl)propionic acid tert-butyl ester; C410798:AR protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000728:Androgens; D054659:Diketopiperazines; D006576:Heterocyclic Compounds, 4 or More Rings; D011944:Receptors, Androgen; D013739:Testosterone