Does the Androgen Receptor (AR)-Regulated Map Kinase Phosphatase 1 (MKP-1) Enhance Castration-Resistant Prostate Cancer Survival under Therapeutic Stress?

摘要

Metastatic castration resistant prostate cancer (mCRPC) is clinically treated with both taxane chemotherapy and androgen pathway modulators. Identification of a mediator of resistance across therapy classes is a critically unmet need and would be a significant innovation in the field. Map Kinase Phophatase 1 (MKP-1, DUSP1) is a known regulator of the stress activated protein kinase cascade that can inhibit the activity of pro-apoptotic Map Kinases JNK and p38. It has an established anti-apoptotic, pro survival role, and has been implicated in chemotherapy resistance in breast cancer models, and is inversely associated with apoptosis in preclinical prostate cancer models. Androgen and glucocorticoid signaling can induce MKP-1 expression; as mCRPC remains driven by androgen receptor signaling, and as mCRPC is often treated adjunctively with corticosteroids, MKP-1 may be a down stream effector of prostate cancer cell survival that facilitates therapy resistance. The work proposed sought to test the hypothesis that MKP-1 plays a role in the development of therapy resistance, independent of therapeutic class, and thus, if inhibited, would potentiate the effects of both hormonal and chemotherapies. To date, significant progress has been made including optimization of MKP-1 protein detection methodologies and the generation of highly bone metastatic CRPC cell lines that can be traced over time with bioluminescence imaging. Ongoing experiments are being undertaken with MKP-1 over expression and knock-down within these cell lines to test for in vivo therapy resistance.