Role of PELP1 in EGFR-ER Signaling Crosstalk in Ovarian Cancer Cells
Final rept. 15 Mar 2006-14 Mar 2009
TEXAS UNIV HEALTH SCIENCE CENTER AT SAN ANTONIO
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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 PELP1MNAR as a novel proto-oncogene for ovarian cancer and showed that PELP1MNAR is 2 to 3 fold overexpressed in 60 of ovarian tumors. To examine the significance of PELP1MNAR in ovarian cancer progression, we have generated model cells that over express PELP1MNAR and ovarian cancer cells in which PELP1MNAR expression is down regulated by stable expression of PELP1MNAR-specific shRNA. Down regulation of PELP1MNAR 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 PELP1MNAR signaling plays a vital role in ovarian cancer cell proliferation and survival, and thus represents a novel therapeutic target.
- Medicine and Medical Research