Altered glucuronidation deregulates androgen dependent response profiles and signifies castration resistance in prostate cancer

Brenna M. Zimmer; Michelle E. Howell; Linlin Ma; Jeffrey R. Enders; Danielle Lehman; Eva Corey; Joseph J. Barycki; Melanie A. Simpson

doi:10.18632/oncotarget.28059

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Research Papers:

Altered glucuronidation deregulates androgen dependent response profiles and signifies castration resistance in prostate cancer

Brenna M. Zimmer, Michelle E. Howell, Linlin Ma, Jeffrey R. Enders, Danielle Lehman, Eva Corey, Joseph J. Barycki and Melanie A. Simpson _

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Oncotarget. 2021; 12:1886-1902. https://doi.org/10.18632/oncotarget.28059

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Abstract

Brenna M. Zimmer1, Michelle E. Howell2, Linlin Ma1, Jeffrey R. Enders3, Danielle Lehman3, Eva Corey4, Joseph J. Barycki1^,3 and Melanie A. Simpson1^,5

1 Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC, USA

2 Department of Biochemistry, University of Nebraska, Lincoln, NE, USA

3 Molecular Education, Technology and Research Innovation Center, North Carolina State University, Raleigh, NC, USA

4 Department of Urology, University of Washington, Seattle, WA, USA

5 Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Correspondence to:

Melanie A. Simpson,

email:

[email protected]

Keywords: prostate cancer; castration resistance; detoxification; UDP-glucose dehydrogenase; patient-derived xenografts

Received: July 05, 2021 Accepted: August 13, 2021 Published: September 14, 2021

Copyright: © 2021 Zimmer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

Glucuronidation controls androgen levels in the prostate and the dysregulation of enzymes in this pathway is associated with castration resistant prostate cancer. UDP-glucose dehydrogenase (UGDH) produces UDP-glucuronate, the essential precursor for glucuronidation, and its expression is elevated in prostate cancer. We compared protein and metabolite levels relevant to the glucuronidation pathway in five prostate cancer patient-derived xenograft models paired with their isogenic counterparts that were selected in vivo for castration resistant (CR) recurrence. All pairs showed changes in UGDH and associated enzymes and metabolites that were consistent with those we found in an isogenic androgen dependent (AD) and CR LNCaP prostate cancer model. Ectopic overexpression of UGDH in LNCaP AD cells blunted androgen-dependent gene expression, increased proteoglycan synthesis, significantly increased cell growth compared to controls, and eliminated dose responsive growth suppression with enzalutamide treatment. In contrast, the knockdown of UGDH diminished proteoglycans, suppressed androgen dependent growth irrespective of androgens, and restored androgen sensitivity in CR cells. Importantly, the knockdown of UGDH in both LNCaP AD and CR cells dramatically sensitized these cells to enzalutamide. These results support a role for UGDH in androgen responsiveness and a target for therapeutic strategies in advanced prostate cancer.

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Research Papers:

Altered glucuronidation deregulates androgen dependent response profiles and signifies castration resistance in prostate cancer

Abstract