Glucocorticoids Induce Stress Oncoproteins Associated with Therapy-Resistance in African American and European American Prostate Cancer Cells

Abstract

Glucocorticoid receptor (GR) is emerging as a key driver of prostate cancer (PCa) progression and therapy resistance in the absence of androgen receptor (AR) signaling. Acting as a bypass mechanism, GR activates AR-regulated genes, although GR-target genes contributing to PCa therapy resistance remain to be identified. Emerging evidence also shows that African American (AA) men, who disproportionately develop aggressive PCa, have hypersensitive GR signaling linked to cumulative stressful life events. Using racially diverse PCa cell lines (MDA-PCa-2b, 22Rv1, PC3, and DU145) we examined the effects of glucocorticoids on the expression of two stress oncoproteins associated with PCa therapy resistance, Clusterin (CLU) and Lens Epithelium-Derived Growth Factor p75 (LEDGF/p75). We observed that glucocorticoids upregulated LEDGF/p75 and CLU in PCa cells. Blockade of GR activation abolished this upregulation. We also detected increased GR transcript expression in AA PCa tissues, compared to European American (EA) tissues, using Oncomine microarray datasets. These results demonstrate that glucocorticoids upregulate the therapy resistance-associated oncoproteins LEDGF/p75 and CLU, and suggest that this effect may be enhanced in AA PCa. This study provides an initial framework for understanding the contribution of glucocorticoid signaling to PCa health disparities.

Twenty years of research on the DFS70/LEDGF autoantibody-autoantigen system: many lessons learned but still many questions

“…In addition, the human papilloma virus (HPV) oncoproteins E6 and E7 stimulate oxidative stress and DFS70/LEDGF expression in HPVpositive cervical cancer [85]. As demonstrated recently by our group, DFS70/LEDGF is also upregulated by androgens and glucocorticoids in PCa cells, and downregulated by knockdown of the glucocorticoid receptor, suggesting its susceptibility to nuclear receptor signaling in cancer cells [91].…”

Genetic ancestry, skin color and social attainment: The four cities study

“…The relationship between skin color, ancestry, and disease is complex and is influenced by cultural norms, history, and behavior [ 21 , 51 , 52 ]. These sociopolitical and personal factors influence disparities in health outcomes among so-called racial and ethnic groups [ 21 , 53 – 56 ]. The correlation between race and disease is largely due to the interaction between an individual’s skin color with society (racism) [ 21 ].…”

“…For example, the association between genetic ancestry, skin color, and blood pressure may be attributed to sociocultural factors related to race and racism [ 53 , 54 , 57 ]. A study on glucocorticoid receptor signaling and stress in African American and European American men with prostate cancer indicated cumulative stressful life events (psychosocial stressors) may play a role in aggressive prostate cancer phenotype and mortality in African American men [ 56 ]. Psychosocial stressors (perceived discrimination) based on race have been shown to be significantly associated with detrimental health outcomes for African American, and Caribbean American adults [ 55 ].…”

Genetic Ancestry Analysis Reveals Misclassification of Commonly Used Cancer Cell Lines

“…In order to promote meaningful and quality health disparities research, there has been a recent interest in incorporating increased racial diversity among human cell lines (17,19,23). Racial classification remains extremely useful for describing general patterns of health as most data are reported by self-identified race (47).…”

“…The examination of experimental outcomes using a racial/ ethnic variety of cell lines exposed to the same conditions is a useful tool to elucidate genes or pathways driving the biological contribution to disease disparities (15,(17)(18)(19). Because genetic tapestries differ within and between populations, it is important to include a variety of cell lines derived from individuals within and between populations in an effort to provide an accurate representation of the genetic variability (20)(21)(22).…”