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Retinoic acid receptor γ is a therapeutically targetable driver of growth and survival in prostate cancer

Petrie, Kevin, Urban‐Wójciuk, Zuzanna, Sbirkov, Yordan, Graham, Amy, Hamann, Annika and Brown, Geoffrey (2020) Retinoic acid receptor γ is a therapeutically targetable driver of growth and survival in prostate cancer. Cancer Reports. ISSN 2573-8348

Item Type: Article

Abstract

Background
Prostate cancer (PC) tissue contains all‐trans retinoic acid (ATRA) at a very low level (10−9 M), at least an order of magnitude lower than in adjacent normal healthy prostate cells or benign prostate hyperplasia. When this is coupled with deregulated expression of the intracellular lipid‐binding proteins FABP5 and CRABP2 that is frequently found in PC, this is likely to result in the preferential delivery of ATRA to oncogenic PPARβ/δ rather than retinoic acid receptors (RARs). There are three isotypes of RARs (RARα, RARβ, and RARγ) and recent studies have revealed discrete physiological roles. For example, RARα and RARγ promote differentiation and self‐renewal, respectively, which are critical for proper hematopoiesis.

Aims
We have previously shown that ATRA stimulates transactivation of RARγ at sub‐nanomolar concentrations (EC50 0.24 nM), whereas an 80‐fold higher concentration was required for RARα‐mediated transactivation (EC50 19.3 nM). Additionally, we have shown that RAR pan‐antagonists inhibit the growth of PC cells (at 16‐34 nM). These findings, together with the low level of ATRA in PC, led us to hypothesize that RARγ plays a role in PC pathogenesis and that RARγ‐selective antagonism may be an effective treatment.

Methods and results
We found that concentrations of 10−9 M and below of ATRA promoted survival/proliferation and opposed adipogenic differentiation of human PC cell lines by a mechanism that involves RARγ. We also found that a RARγ‐selective antagonist (AGN205728) potently induced mitochondria‐dependent, but caspase‐independent, cell death in PC cell lines. Furthermore, AGN205728 demonstrated synergism in killing PC cells in combination with cytotoxic chemotherapeutic agents.

Conclusion
We suggest that the use of RARγ‐selective antagonists may be effective in PC (and potentially other cancers), either as a single agent or in combination with cytotoxic chemotherapy.

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Depositing User: Leah Maughan

Identifiers

Item ID: 12703
Identification Number: https://doi.org/10.1002/cnr2.1284
ISSN: 2573-8348
URI: http://sure.sunderland.ac.uk/id/eprint/12703
Official URL: http://dx.doi.org/10.1002/cnr2.1284

Users with ORCIDS

ORCID for Kevin Petrie: ORCID iD orcid.org/0000-0002-9805-9152

Catalogue record

Date Deposited: 20 Oct 2020 11:03
Last Modified: 20 Oct 2020 11:03

Contributors

Author: Kevin Petrie ORCID iD
Author: Zuzanna Urban‐Wójciuk
Author: Yordan Sbirkov
Author: Amy Graham
Author: Annika Hamann
Author: Geoffrey Brown

University Divisions

Faculty of Health Sciences and Wellbeing > School of Medicine

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