Abstract C43: Glucocorticoid-mediated upregulation of stress oncoproteins: Implications for prostate cancer health disparities

Abstract

Abstract Prostate cancer (PCa) presents the greatest US cancer health disparity in terms of incidence and mortality, disproportionately affecting African American (AA) men. The biological characteristics of prostate tumors are exaggerated in AA men compared to European American (EA) men at time of diagnosis, including higher PSA levels, higher Gleason scores, and advanced tumor stage. These factors influence the relatively poorer prognosis and worse overall survival rate observed in AA men. There is, however, a gap in our understanding of the mechanisms underlying increased PCa aggressiveness in AA men; therefore, there is a critical need to identify biological determinants contributing to PCa mortality disparities. Glucocorticoids—a type of steroid hormone produced in the human biological response to stress—have been implicated as driving factors in PCa progression. The underlying mechanism involves endogenous glucocorticoid (cortisol) binding to its glucocorticoid receptor (GR) and activating genes that promote tumor aggressiveness and therapy resistance. Results from phase 3 of clinical trial AFFIRM revealed that men receiving glucocorticoids to reduce the negative side effects of advanced PCa and treatment showed a significantly worse survival rate than those not receiving glucocorticoids. A clinical dilemma exists as glucocorticoids, important in the palliative care of PCa patients are now emerging as accelerators of disease progression and shortened survival. Chronically elevated levels of cortisol, which promote metabolic disorders, have been documented in AA men compared to EA men. This unhealthy cortisol production has been linked to stressful life events, which occur more frequently in the AA population. In addition, AAs are more sensitive to glucocorticoid exposure than EAs. These observations support the hypothesis that chronic stress leading to elevated cortisol in AA men may contribute to PCa health disparities. This study focused on examining the effects of glucocorticoid agonists and antagonists on the expression of stress oncoproteins, particularly LEDGF/p75 and clusterin, which are upregulated in PCa tumors and promote features of tumor aggressiveness, including resistance to clinically relevant taxanes used for advanced PCa treatment. We exposed a racially diverse panel of PCa cell lines, MDA-PCa-2b, 22Rv1, PC3, and DU145, to glucocorticoids (cortisol and dexamethasone), and observed by immunoblotting a time and dose-dependent upregulation of LEDGF/p75 and clusterin, particularly and more robustly in AA cells. Treatment of cells with mifepristone, a GR antagonist, attenuated this glucocorticoid-induced upregulation. In addition, shRNA-mediated depletion of LEDGF/p75 in PC3 cells resulted in decreased GR expression, suggesting a functional interplay between these two proteins in PCa cells. Interestingly, we also observed, using ELISA, increased circulation levels of LEDGF/p75 in AA PCa patients compared to EA patients and non-PCa controls, suggesting that this stress oncoprotein might play a more prominent role in AA PCa patients. These findings imply that activation of GR-signaling by glucocorticoids contributes to the activation of stress survival pathways associated with PCa aggressiveness. These results add to the emerging contribution of GR signaling in PCa, particularly in the context of PCa health disparities. Citation Format: Leanne Woods-Burnham, Arthur Love, Christina K. Cajigas-Du Ross, Anamika Basu, Laura Stiel, Susanne Montgomery, Colwick Wilson, Carlos A. Casiano. Glucocorticoid-mediated upregulation of stress oncoproteins: Implications for prostate cancer health disparities. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr C43.