Study will determine the potential role of SerpinA6 (Corticosteroid-Binding Globulin; a carrier of glucocorticoids in the plasma) in prostate cancer progression. In castrate resistant prostate cancer (CRPC) patients, presence of higher levels of IL-6 has been observed. Our preliminary data on CRPC prostate cancer cells represented decreasing SerpinA6 levels after IL-6 dose response treatment. Circulatory levels of SerpinA6 believed to keep the steroids inactive and regulate the amount of free hormone acting on target tissues. SerpinA6 contains a single binding site for glucocorticoid (GC) and progesterone, and both binds (80?90%) to SerpinA6 with high affinity. Active role of SerpinA6 is in bioavailability of GC for the glucocorticoid receptor, local delivery, and/or cellular signal transduction of GCs, only the unbound (free) fraction of GCs are biologically active. Moreover reports suggest that SerpinA6 promoter is transcriptionally regulated via the glucocorticoid receptor (GR), this suggest that GR has significant role in SerpinA6 regulation. Increasing GR levels in prostate and increasing IL- 6 level in prostate (due to castration) decreases SerpinA6 expression. Evidence in castrate resistant prostate cancer (CRPC) patients suggests, GR compensates for the lack of androgen receptor (AR) activity in prostate cancer patients. Additionally reports suggest GR has significant role in prostate cancer cells survival and cell cycle regulation. Encouraging preliminary data suggest AR and GR directly or indirectly linked with transcription factor FOXO3a in regulation. We observed increase IL-6 levels in CRPC prostate cancer cells decrease FOXO3a expression. Goal of this research project is to determine the role of SerpinA6 in progression of prostate cancer. Therefore, increased GCs in CRPC patients due to inappropriate SerpinA6 level would increase GR expression in the prostate tissue, which will promote cell survival and proliferation. The proposed mechanistic study, in in-vitro and in-vivo model system will determine whether decrease SerpinA6 levels in CRPC cells have potential to promote prostate cancer progression. Our long term goal is to develop SerpinA6 as potential target for prostate cancer progression, and to determine SerpinA6 modulation as a therapeutic target to inhibit prostate cancer progression. Public Health Significance: There is an immediate need for an effective and clinically relevant target, which has potential role in CRPC progression. We need to have specific and selective targets for progressive events and also need to have the therapeutic approaches to modulate these targets and prevent the further progression of prostate cancer.
Proposal will determine the potential role of SerpinA6 and glucocorticoid receptor (GR) in prostate cancer progression. Reports in drug resistant prostate cancer and castrate resistant prostate cancer (CRPC) patients demonstrated increased glucocorticoid (GC), GR and IL-6 expressions, which promotes prostate cancer progression. We observed IL-6 treatment to CRPC cells decreases SerpinA6 expression. SerpinA6 plays significant role in steroid hormone regulation, glucocorticoids binding and its local delivery. In CRPC patients decreasing SerpinA6 levels wouldn't be enough to bind increasing GC and GR levels, which are known to promote cell survival and proliferation in prostate cancer. Using in-vitro and in in-vivo model systems (orthotopic prostate cancer mouse model and Transgenic Adenocarcinoma of the Mouse Prostate; TRAMP) we will determine the potential role of SerpinA6 in prostate cancer progression. Results obtained from the proposed studies will provide the critical data to further modulate the decreasing levels of SerpinA6 in CRPC as a means to prevent prostate cancer progression.
