Role of PELP1 in EGFR-ER Signaling Crosstalk in Ovarian Cancer Cells

摘要

Ovarian cancer is an endocrine-related cancer, but it remains unknown which hormone-regulated mechanisms are critical in ovarian cancer pathogenesis. In this study, we have identified nuclear hormonal receptor coregulator, Proline-, glutamic acid-, and leucine-rich protein-1 (PELP1/MNAR) as a novel proto-oncogene for ovarian cancer and showed that PELP1/MNAR is 2 to 3 fold overexpressed in 60% of ovarian tumors. To examine the significance of PELP1/MNAR in ovarian cancer progression, we have generated model cells that over express PELP1/MNAR and ovarian cancer cells in which PELP1/MNAR expression is down regulated by stable expression of PELP1/MNAR-specific shRNA. Down regulation of PELP1/MNAR in cancerous ovarian model cells (OVCAR3) resulted in reduced proliferation, affected the magnitude of c-Src and AKT signaling and reduced tumorigenic potential of ovarian cancer cells in a nude mouse model. PELP1 knock down affected EGF mediated activation of cytoskeletal reorganization affected tumor cell migration and increased sensitivity of chemotherapy drugs. We have generated PELP1siRNA nanoliposomes and demonstrated the feasibility of using them as novel therapeutics to reduce PELP1 expression in vivo. Collectively these results suggest that PELP1/MNAR signaling plays a vital role in ovarian cancer cell proliferation and survival, and thus represents a novel therapeutic target.