Abstract 5285: Glucocorticoid-mediated upregulation of stress oncoproteins: implications for prostate cancer health disparities
Authors: Woods-Burnham Leanne , Love Arthur , Ross Christina K. Cajigas-Du , Stiel Laura , Sanchez Evelyn S. , Amponsah Kwame , Montgomery Susanne , Wilson Colwick , Casiano Carlos A. 
Published: July 2017

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. The mechanisms underlying increased PCa aggressiveness in AA men are not fully understood; therefore, there is a critical need to identify biological determinants contributing to PCa mortality disparities. Glucocorticoids—a type of stress hormone—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. 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 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, AA men are more sensitive to glucocorticoid exposure than EA men. 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 (Lens epithelial-derived growth factor of 75 kd) and CLU (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 GR, LEDGF/p75 and CLU, particularly and more robustly in AA cells. Treatment of cells with mifepristone, a GR antagonist, attenuated this glucocorticoid-induced upregulation. In addition, siRNA- and shRNA-knockdown 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 and chemoresistance. 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, Laura Stiel, Evelyn S. Sanchez, Kwame Amponsah, Susanne Montgomery, Colwick Wilson, Carlos A. Casiano. Glucocorticoid-mediated upregulation of stress oncoproteins: implications for prostate cancer health disparities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5285. doi:10.1158/1538-7445.AM2017-5285