Abstract 5043: Glucocorticoids trigger GR-mediated expression of the chemoresistance-associated oncoproteins LEDGF/p75 and Clusterin: Implications for prostate cancer health disparities

Prostate cancer (PCa) is more aggressive in African American (AA) men compared to European American (EA) men, resulting in increased incidence and mortality disparities. There is a critical need to identify biological determinants contributing to these disparities. Glucocorticoids—a type of stress hormone—have recently been implicated as biological factors driving PCa progression and response to therapy. The underlying mechanism involves endogenous glucocorticoid binding to its receptor (GR), prompting GR to transcriptionally activate genes that are typically androgen-regulated and that promote tumor aggressiveness and therapy resistance. However, a clinical dilemma exists as glucocorticoids, necessary in the palliative care of PCa patients, are now emerging as accelerators of disease progression. In addition, AA men have chronically elevated levels of glucocorticoids linked to stressful life events, and are also hypersensitive to glucocorticoid exposure. We examined the effects of glucocorticoids on the activation of the stress oncoproteins LEDGF/p75 (Lens Epithelium Derived Growth Factor of 75kd) and CLU (Clusterin), linked by our group and others to prostate tumor aggressivenes and taxane resistance. Our goal is to establish the interplay between glucocorticoids and the expression of these proteins in the context of PCa health disparities. We hypothesized that LEDGF/p75 and CLU may be induced by glucocorticoids through GR in PCa cells. Treatment of a racially diverse panel PCa cell lines (MDA-PCa-2b [AA], 22Rv1 [AA/EA], PC3 [EA], and DU145 [EA]) with 10nM cortisol or dexamethasone for up to 48h significantly upregulated both transcript and protein levels of LEDGF/p75 and CLU. This upregulation was more robust in the AA cell lines. Depletion of GR with siRNAs abrogated dexamethasone-induced upregulation of LEDGF/p75 and CLU. Pharmacological inhibition of GR with mifepristone, in the presence of dexamethasone, also abrogated the induction of these proteins in a cell type-dependent manner. We also observed that dexamethasone exposure increased cell migration, a characteristic of tumor aggressiveness. Furthermore, using an ELISA platform we detected increased serum levels of LEDGF/p75 in AA PCa patients, as well as increased levels of CLU in non-PCa AA men, compared to EA patients and controls. These findings show that glucocorticoids induce the expression of oncoproteins associated with PCa aggressiveness and therapy resistance, and this upregulation may occur more robustly in AA men, priming them to develop highly aggressive PCa tumors. Citation Format: Leanne Woods-Burnham, Christina K. Cajigas-Du Ross, Anamika Basu, Evelyn S. Sanchez, Arthur Love, Carlos A. Casiano. Glucocorticoids trigger GR-mediated expression of the chemoresistance-associated oncoproteins LEDGF/p75 and Clusterin: Implications for prostate cancer health disparities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5043.