Dataset Information

3D structure of the transporter ABCG2-What's new?

ABSTRACT: ABCG2 belongs to the ABC transporter superfamily and functions as a poly-specific efflux pump. As it can transport a broad spectrum of substrates out of cells, ABCG2 is thought to alter the pharmacokinetics of drugs applied to treat certain diseases. Especially, its potential to induce resistance to chemotherapy is currently the object of intense research. To foster understanding of mechanisms relevant for substrate recognition and selection of ABCG2 substrates and to finally develop selective therapeutic modulators (e.g. inhibitors) of ABCG2 transport activity, it is important to further explore the precise 3D structure of the transporter. While efforts to elucidate the three-dimensional structure of ABCG2 using X-ray crystal structure analysis have not been successful so far, high-resolution cryo-electron microscopy-based investigations have revealed exciting new insights into the structure and function of the transporter. In this review, we will focus on these seminal publications to summarize the current understanding of tertiary and quaternary structure, homodimerization or oligomerization, and functions of the ABCG2 transporter protein.

SUBMITTER: Eckenstaler R

PROVIDER: S-EPMC7060357 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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3D structure of the transporter ABCG2-What's new?

Eckenstaler Robert R Benndorf Ralf A RA

British journal of pharmacology 20200211 7

ABCG2 belongs to the ABC transporter superfamily and functions as a poly-specific efflux pump. As it can transport a broad spectrum of substrates out of cells, ABCG2 is thought to alter the pharmacokinetics of drugs applied to treat certain diseases. Especially, its potential to induce resistance to chemotherapy is currently the object of intense research. To foster understanding of mechanisms relevant for substrate recognition and selection of ABCG2 substrates and to finally develop selective t ...[more]

PMID: 31985041

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Project description: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.ImplicationsThis 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.

Dataset Information

3D structure of the transporter ABCG2-What's new?

Publications

3D structure of the transporter ABCG2-What's new?

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