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

Background: Prostate cancer (PC) tissue contains all-transretinoic 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 PPAR beta/delta rather than retinoic acid receptors (RARs). There are three isotypes of RARs (RAR alpha, RAR beta, and RAR gamma) and recent studies have revealed discrete physiological roles. For example, RAR alpha and RAR gamma promote differentiation and self-renewal, respectively, which are critical for proper hematopoiesis. Aims: We have previously shown that ATRA stimulates transactivation of RAR gamma at sub-nanomolar concentrations (EC50 0.24 nM), whereas an 80-fold higher concentration was required for RAR alpha-mediated transactivation (EC(50)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 RAR gamma plays a role in PC pathogenesis and that RAR gamma-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 RAR gamma. We also found that a RAR gamma-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 RAR gamma-selective antagonists may be effective in PC (and potentially other cancers), either as a single agent or in combination with cytotoxic chemotherapy.