skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Contrasting roles of the ABCG2 Q141K variant in prostate cancer

Abstract

ABCG2 is a membrane transport protein that effluxes growth-promoting molecules, such as folates and dihydrotestosterone, as well as chemotherapeutic agents. Therefore it is important to determine how variants of ABCG2 affect the transporter function in order to determine whether modified treatment regimens may be necessary for patients harboring ABCG2 variants. Previous studies have demonstrated an association between the ABCG2 Q141K variant and overall survival after a prostate cancer diagnosis. We report here that in patients with recurrent prostate cancer, those who carry the ABCG2 Q141K variant had a significantly shorter time to PSA recurrence post-prostatectomy than patients homozygous for wild-type ABCG2 (P=0.01). Transport studies showed that wild-type ABCG2 was able to efflux more folic acid than the Q141K variant (P<0.002), suggesting that retained tumoral folate contributes to the decreased time to PSA recurrence in the Q141K variant patients. In a seemingly conflicting study, it was previously reported that docetaxel-treated Q141K variant prostate cancer patients have a longer survival time. We found this may be due to less efficient docetaxel efflux in cells with the Q141K variant versus wild-type ABCG2. In human prostate cancer tissues, confocal microscopy revealed that all genotypes had a mixture of cytoplasmic and plasma membrane staining, withmore » noticeably less staining in the two homozygous KK patients. In conclusion, the Q141K variant plays contrasting roles in prostate cancer: 1) by decreasing folate efflux, increased intracellular folate levels result in enhanced tumor cell proliferation and therefore time to recurrence decreases; and 2) in patients treated with docetaxel, by decreasing its efflux, intratumoral docetaxel levels and tumor cell drug sensitivity increase and therefore patient survival time increases. Taken together, these data suggest that a patient's ABCG2 genotype may be important when determining a personalized treatment plan. - Highlights: • The presence of ABCG2 Q141K variant decreases time to PSA recurrence. • Cells expressing the Q141K variant retain more folic acid than wild type. • Cells expressing the Q141K variant are more sensitive to docetaxel. • ABCG2 protein is repressed miR-519c and/or miR-520h in prostate cancer cell lines.« less

Authors:
 [1];  [1];  [2];  [1];  [2];  [1];  [2]
  1. Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA (United States)
  2. (United States)
Publication Date:
OSTI Identifier:
22649853
Resource Type:
Journal Article
Resource Relation:
Journal Name: Experimental Cell Research; Journal Volume: 354; Journal Issue: 1; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANIMAL TISSUES; CELL PROLIFERATION; DIAGNOSIS; FOLIC ACID; GENOTYPE; HUMAN POPULATIONS; MEMBRANE TRANSPORT; MEMBRANES; MICROSCOPY; NEOPLASMS; PATIENTS; PROSTATE; PROTEINS; SENSITIVITY; SURVIVAL TIME; TUMOR CELLS

Citation Formats

Sobek, Kathryn M., Cummings, Jessica L., Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, Bacich, Dean J., Department of Urology, University of Texas Health Science Center, San Antonio, TX, O’Keefe, Denise S., E-mail: OKeefeD@uthscsa.edu, and Department of Urology, University of Texas Health Science Center, San Antonio, TX. Contrasting roles of the ABCG2 Q141K variant in prostate cancer. United States: N. p., 2017. Web. doi:10.1016/J.YEXCR.2017.03.020.
Sobek, Kathryn M., Cummings, Jessica L., Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, Bacich, Dean J., Department of Urology, University of Texas Health Science Center, San Antonio, TX, O’Keefe, Denise S., E-mail: OKeefeD@uthscsa.edu, & Department of Urology, University of Texas Health Science Center, San Antonio, TX. Contrasting roles of the ABCG2 Q141K variant in prostate cancer. United States. doi:10.1016/J.YEXCR.2017.03.020.
Sobek, Kathryn M., Cummings, Jessica L., Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, Bacich, Dean J., Department of Urology, University of Texas Health Science Center, San Antonio, TX, O’Keefe, Denise S., E-mail: OKeefeD@uthscsa.edu, and Department of Urology, University of Texas Health Science Center, San Antonio, TX. Mon . "Contrasting roles of the ABCG2 Q141K variant in prostate cancer". United States. doi:10.1016/J.YEXCR.2017.03.020.
@article{osti_22649853,
title = {Contrasting roles of the ABCG2 Q141K variant in prostate cancer},
author = {Sobek, Kathryn M. and Cummings, Jessica L. and Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA and Bacich, Dean J. and Department of Urology, University of Texas Health Science Center, San Antonio, TX and O’Keefe, Denise S., E-mail: OKeefeD@uthscsa.edu and Department of Urology, University of Texas Health Science Center, San Antonio, TX},
abstractNote = {ABCG2 is a membrane transport protein that effluxes growth-promoting molecules, such as folates and dihydrotestosterone, as well as chemotherapeutic agents. Therefore it is important to determine how variants of ABCG2 affect the transporter function in order to determine whether modified treatment regimens may be necessary for patients harboring ABCG2 variants. Previous studies have demonstrated an association between the ABCG2 Q141K variant and overall survival after a prostate cancer diagnosis. We report here that in patients with recurrent prostate cancer, those who carry the ABCG2 Q141K variant had a significantly shorter time to PSA recurrence post-prostatectomy than patients homozygous for wild-type ABCG2 (P=0.01). Transport studies showed that wild-type ABCG2 was able to efflux more folic acid than the Q141K variant (P<0.002), suggesting that retained tumoral folate contributes to the decreased time to PSA recurrence in the Q141K variant patients. In a seemingly conflicting study, it was previously reported that docetaxel-treated Q141K variant prostate cancer patients have a longer survival time. We found this may be due to less efficient docetaxel efflux in cells with the Q141K variant versus wild-type ABCG2. In human prostate cancer tissues, confocal microscopy revealed that all genotypes had a mixture of cytoplasmic and plasma membrane staining, with noticeably less staining in the two homozygous KK patients. In conclusion, the Q141K variant plays contrasting roles in prostate cancer: 1) by decreasing folate efflux, increased intracellular folate levels result in enhanced tumor cell proliferation and therefore time to recurrence decreases; and 2) in patients treated with docetaxel, by decreasing its efflux, intratumoral docetaxel levels and tumor cell drug sensitivity increase and therefore patient survival time increases. Taken together, these data suggest that a patient's ABCG2 genotype may be important when determining a personalized treatment plan. - Highlights: • The presence of ABCG2 Q141K variant decreases time to PSA recurrence. • Cells expressing the Q141K variant retain more folic acid than wild type. • Cells expressing the Q141K variant are more sensitive to docetaxel. • ABCG2 protein is repressed miR-519c and/or miR-520h in prostate cancer cell lines.},
doi = {10.1016/J.YEXCR.2017.03.020},
journal = {Experimental Cell Research},
number = 1,
volume = 354,
place = {United States},
year = {Mon May 01 00:00:00 EDT 2017},
month = {Mon May 01 00:00:00 EDT 2017}
}