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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Cancer Biology and Translational Studies

Identification of Genes Required for Enzalutamide Resistance in Castration-Resistant Prostate Cancer Cells In Vitro

Sarah E. Kohrt, Wisam N. Awadallah, Robert A. Phillips III, Thomas C. Case, Renjie Jin, Jagpreet S. Nanda, Xiuping Yu, Peter E. Clark, Yajun Yi, Robert J. Matusik, Philip D. Anderson and Magdalena M. Grabowska
Sarah E. Kohrt
1Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio.
2Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
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  • ORCID record for Sarah E. Kohrt
Wisam N. Awadallah
2Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
3Department of Urology, Case Western Reserve University, Cleveland, Ohio.
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Robert A. Phillips III
4Biological Sciences, Salisbury University, Salisbury, Maryland.
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Thomas C. Case
5Department of Urology, Vanderbilt University Medical Center, Nashville, Tennessee.
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Renjie Jin
5Department of Urology, Vanderbilt University Medical Center, Nashville, Tennessee.
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Jagpreet S. Nanda
2Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
3Department of Urology, Case Western Reserve University, Cleveland, Ohio.
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Xiuping Yu
6Department of Biochemistry, Louisiana State University Health Shreveport, Shreveport, Louisiana.
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Peter E. Clark
7Department of Urology, Levine Cancer Center/Atrium Health, Charlotte, North Carolina.
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Yajun Yi
8Quality, Safety and Risk Prevention, Vanderbilt University Medical Center, Nashville, Tennessee.
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Robert J. Matusik
5Department of Urology, Vanderbilt University Medical Center, Nashville, Tennessee.
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Philip D. Anderson
4Biological Sciences, Salisbury University, Salisbury, Maryland.
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Magdalena M. Grabowska
1Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio.
2Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
3Department of Urology, Case Western Reserve University, Cleveland, Ohio.
9Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio.
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  • ORCID record for Magdalena M. Grabowska
  • For correspondence: mmg126@case.edu
DOI: 10.1158/1535-7163.MCT-20-0244 Published February 2021
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Abstract

Castration-resistant prostate cancer can be treated with the antiandrogen enzalutamide, but responses and duration of response are variable. To identify genes that support enzalutamide resistance, we performed a short hairpin RNA (shRNA) screen in the bone-homing, castration-resistant prostate cancer cell line, C4-2B. We identified 11 genes (TFAP2C, CAD, SPDEF, EIF6, GABRG2, CDC37, PSMD12, COL5A2, AR, MAP3K11, and ACAT1) whose loss resulted in decreased cell survival in response to enzalutamide. To validate our screen, we performed transient knockdowns in C4-2B and 22Rv1 cells and evaluated cell survival in response to enzalutamide. Through these studies, we validated three genes (ACAT1, MAP3K11, and PSMD12) as supporters of enzalutamide resistance in vitro. Although ACAT1 expression is lower in metastatic castration-resistant prostate cancer samples versus primary prostate cancer samples, knockdown of ACAT1 was sufficient to reduce cell survival in C4-2B and 22Rv1 cells. MAP3K11 expression increases with Gleason grade, and the highest expression is observed in metastatic castration-resistant disease. Knockdown of MAP3K11 reduced cell survival, and pharmacologic inhibition of MAP3K11 with CEP-1347 in combination with enzalutamide resulted in a dramatic increase in cell death. This was associated with decreased phosphorylation of AR-Serine650, which is required for maximal AR activation. Finally, although PSMD12 expression did not change during disease progression, knockdown of PSMD12 resulted in decreased AR and AR splice variant expression, likely contributing to the C4-2B and 22Rv1 decrease in cell survival. Our study has therefore identified at least three new supporters of enzalutamide resistance in castration-resistant prostate cancer cells in vitro.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2021;20:398–409

  • Received March 29, 2020.
  • Revision received September 11, 2020.
  • Accepted November 17, 2020.
  • Published first December 9, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 20 (2)
February 2021
Volume 20, Issue 2
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Identification of Genes Required for Enzalutamide Resistance in Castration-Resistant Prostate Cancer Cells In Vitro
Sarah E. Kohrt, Wisam N. Awadallah, Robert A. Phillips III, Thomas C. Case, Renjie Jin, Jagpreet S. Nanda, Xiuping Yu, Peter E. Clark, Yajun Yi, Robert J. Matusik, Philip D. Anderson and Magdalena M. Grabowska
Mol Cancer Ther February 1 2021 (20) (2) 398-409; DOI: 10.1158/1535-7163.MCT-20-0244

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Identification of Genes Required for Enzalutamide Resistance in Castration-Resistant Prostate Cancer Cells In Vitro
Sarah E. Kohrt, Wisam N. Awadallah, Robert A. Phillips III, Thomas C. Case, Renjie Jin, Jagpreet S. Nanda, Xiuping Yu, Peter E. Clark, Yajun Yi, Robert J. Matusik, Philip D. Anderson and Magdalena M. Grabowska
Mol Cancer Ther February 1 2021 (20) (2) 398-409; DOI: 10.1158/1535-7163.MCT-20-0244
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Molecular Cancer Therapeutics
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