Characterizing glucocorticoid receptor in metastatic castration resistant prostate cancer
Kahn, Matthew Adam
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The purpose of this paper is to characterize the glucocorticoid receptor (GR) signaling and relevance in the context of enzalutamide resistant prostate cancer cells. Enzalutamide is a drug that functions to dampen androgen receptor (AR) signaling, thus inhibiting cancer dependency on the receptor protein. Although the application of the drug reduces AR signaling in these cancer cells, an alternate pathway involving GR signaling may be upregulated as a compensatory bypass mechanism. Therefore, it possible that GR assumes the role of AR and facilitates tumor growth by promoting the expression of genes regulated by AR. To analyze how GR operates, we analyzed GR signaling in enzalutamide resistant metastatic prostate cancer cell lines. We assessed protein levels of AR and GR as well as mRNA expression of various AR targets. Our results illustrate the expected downregulation of AR and upregulation of GR in enzalutamide resistant cells. Furthermore, some canonical AR targets like prostate specific antigen (PSA), Prostate Specific Membrane Antigen (PSMA) and Prostatic Acid Phosphatase (PAP) were inhibited by a novel GR inhibitor. Thus, this GR inhibitor could be used in combination with enzalutamide and create a more potent AR signaling blockade. Prostate cancer is a very problematic disease in men and becomes especially challenging to treat during the metastatic stage as they are non-sensitive to anti-androgens. The significance of understanding how GR functions, as well as the potential benefit of blocking GR signaling, may provide insight into novel drugs and agents that could specifically target these pathways, control and mitigate cancer growth, and prolong the lives of patients.