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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.

SUBMITTER: Sabnis NG

PROVIDER: S-EPMC5290130 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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The Efflux Transporter ABCG2 Maintains Prostate Stem Cells.

Sabnis Neha G NG Miller Austin A Titus Mark A MA Huss Wendy J WJ

Molecular cancer research : MCR 20161117 2

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 ...[more]

PMID: 27856956

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Project description:High expression of aldehyde dehydrogenase1A1 (ALDH1A1) is observed in many organs and tumors and may identify benign and cancer stem cell populations.In the current study, the stem cell characteristics were determined in cells isolated from human prostate cell lines and clinical prostate specimens based upon the ALDEFLUOR™ assay. Cells isolated based on the ALDEFLUOR™ assay were compared to cells isolated based on ATP binding cassette transporter G2 (ABCG2) activity using the side population assay. To test for stem cell characteristics of self-renewal and multipotency, cells with high and low ALDH1A1 activity, based on the ALDEFLUOR™ assay (ALDHHi and ALDH Low), were isolated from prostate clinical specimens and were recombined with rat urogenital sinus mesenchyme to induce prostate gland formation.The percentage of ALDH Hi cells in prostate cell lines (RWPE-1, RWPE-2, CWR-R1, and DU-145) was 0.5 to 6%, similarly in non-tumor and tumor clinical specimens the percentage of ALDH Hi cells was 0.6 to 4%. Recombinants using ALDH Hi cells serially generated prostate tissue up to three generations with as few as 250 starting cells. Immunohistochemical analysis of the recombinants using ALDHHi cells contained prostatic glands frequently expressing androgen receptor (AR), p63, chromogranin A, ALDH1A1, ABCG2, and prostate specific antigen (PSA), compared to their ALDH Low counterparts. Inhibition of ALDH resulted in the reduction of sphere formation capabilities in the CWR-R1, but not in the RWPE-2 and DU-145, prostate cell lines. ABCG2 inhibition resulted in a more robust decrease of sphere formation in androgen sensitive cell lines, CWR-R1 and RWPE-2, but not androgen insensitive DU-145. ALDH1A1 expression was enriched in ALDH Hi cells and non-side population cells. ABCG2 expression was only enriched in side population cells.The percentage of ALDHHi cells in prostate cell lines and prostate tissue was consistently higher compared to cells with high ABCG2 activity, identified with the side population assay. The expression of the stem and differentiation markers indicates the ALDH Hi recombinants contained cells with self-renewal and multipotency activity. When the two assays were directly compared, cells with the side population phenotype demonstrated more stem cell potential in the tissue recombination assay compared to ALDH Hi cells. The increased stem cell potential of side population cells in the tissue recombination assay and the decrease in sphere formation when ABCG2 is inhibited indicates that the side population enriches for prostate stem cells.

Dataset Information

The Efflux Transporter ABCG2 Maintains Prostate Stem Cells.

Publications

The Efflux Transporter ABCG2 Maintains Prostate Stem Cells.

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