Interleukin-6 increases glucocorticoid inactivation in a castration resistant prostate cancer cell line model

Prostate cancer is the second leading cause of cancer deaths in men in the United States. It is dependent on androgen receptor (AR) signaling and initially is responsive to therapies blocking AR signaling. Unfortunately, it is common for the cancer to reoccur and become resistant to these therapies and become a form known as castration resistant prostate cancer. This resistance to AR blockers is in part mediated by the glucocorticoid receptor (GR) taking over the regulation of AR-target genes driving proliferation. As shown by our group and others, this GR take over in AR blocker resistant tumors is in part due to increases in GR levels and due to loss of the glucocorticoid-inactivating enzyme 11betaHSD2. Studying the regulation of the tumor-specific levels of the active glucocorticoid, cortisol, is essential as they determine local GR activity and are hence tied to therapeutic resistance. In this work, we set out to determine how cytokines regulate 11betaHSD2 activity and affect glucocorticoid levels in prostate cancer. Using a cell line model of castration resistant prostate cancer (VCaP) and tracing of radiolabeled steroids by High Performance Liquid Chromatography, we show that interleukin-6 (IL-6) increases 11betaHSD2 activity, promoting metabolic inactivation of glucocorticoids. We show that interleukin-6 increases transcript levels of HSD11B2 (encoding 11betaHSD2) and 11betaHSD2 protein abundance indicating that IL-6 drives increased glucocorticoid inactivation by upregulating HSD11B2 at the transcriptional level. Using transient siRNA knockdowns and selective, pharmacological inhibitors, we show that blocking JAK1/2, gp130, and STAT3 results in reversal of this glucocorticoid inactivation and are therefore required signaling elements that mediate the interleukin-6 induced upregulation of HSD11B2 expression, protein level and activity in VCaP cells. Taken together, we have discovered interleukin-6 and JAK/STAT signaling as a potential new regulator of glucocorticoid metabolism in prostate cancer. Further work will elicit the physiological and therapeutic implications in the context of disease progression and therapy resistance. Ultimately, this research aims to deepen the understanding of glucocorticoid metabolism regulation in prostate cancer and its role in disease escalation and treatment responsiveness.