Abstract D116: Glucocorticoid receptor interacts with beta-catenin to promote stemness and therapy resistance in prostate cancer cells

Abstract

Abstract Prostate cancer (PCa) is the most commonly diagnosed male cancer, with men of African ancestry showing a disproportionately high incidence and mortality. There is increasing evidence that glucocorticoid signaling through glucocorticoid receptor (GR) is amplified in African American men due to cumulative life stress, and that GR signaling is a key driver of resistance to androgen-targeted therapy, radiotherapy, and taxane chemotherapy in advanced PCa. Recent studies indicate that GR also promotes in PCa cells the formation of tumorspheres, a property of cancer stem cells (CSC); however, the mechanisms remain unclear. CSCs are intrinsically resistant to therapies due to their low-frequency, expression of transporters and efflux pumps, quiescent cell cycle and metabolic profile. Our previous studies demonstrated that docetaxel (DTX)-resistant PCa cells exhibit increased capacity for CSC-like properties, suggesting that these properties contribute to chemoresistance. Like GR, beta-catenin is overexpressed in metastatic and therapy-resistant tumors, and is considered a key regulator of cancer stemness and androgen-targeted therapy resistance. Thus, we hypothesized that GR may interact with beta-catenin in PCa cells to support stemness and chemoresistance. Using whole-cell and nuclear co-immunoprecipitation, we demonstrated the interaction between GR and beta-catenin in several DTX-sensitive and -resistant PCa cell line pairs. Pharmacological inhibition of GR using the selective inhibitor CORT-108297 with concomitant inhibition of beta-catenin using the small molecule inhibitor MSAB significantly enhanced DTX cytotoxicity in resistant PCa cells grown in both adherent and spheroid cultures. The BET bromodomain inhibitor JQ1, an antagonist of enhancer-mediated GR upregulation, also significantly reduced tumorsphere formation and stemness in DTX-resistant PCa cells. In order to gain insights into transcriptomic profiles activated by GR signaling that may contribute to stemness and therapy resistance, we performed RNA sequencing in a racially diverse panel of PCa cell lines (MDA-PCa-2b, VCaP, 22RV1, and PC3) treated with and without dexamethasone, a potent glucocorticoid. We observed that the African American cell line MDA-PCa-2b yielded the largest number of differentially regulated genes, perhaps due to the ability of dexamethasone to signal through both AR and GR in this particular cell line. RNAseq data is currently being mined and validated in cellular models treated with glucocorticoids or androgens, in the presence or absence of anti-GR or anti-androgen inhibitors, in order to identify GR-regulated genes. Our results offer novel insights into mechanisms by which GR signaling may influence tumorsphere formation and stemness, and suggest that combinatorial targeting of GR and beta-catenin could be a promising therapeutic strategy to overcome PCa therapy resistance and consequently reduce PCa mortality and its racial disparities. Citation Format: Shannalee R Martinez, Evelyn S Sanchez-Hernandez, Xin Chen, Alfonso M Duran, Charles H Wang, Carlos A Casiano. Glucocorticoid receptor interacts with beta-catenin to promote stemness and therapy resistance in prostate cancer cells [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D116.