Abstract 3669: PELP1: A novel therapeutic target for ovarian cancer progression and metastasis

Abstract

Abstract Ovarian cancer remains a major threat to women's health, especially because of the difficulty in early diagnosis and due to prevalent metastasis. There is critical need to identify novel targets that can be used to curb the progression and metastasis of ovarian cancer. Recent studies implicated a role for nuclear receptors (NR) and their coregulators in ovarian cancer progression and expression of NR-coregulators is shown to be deregulated in ovarian cancer. In this study, we examined whether NR coregulator PELP1 contributes to progression and metastatic potential of ovarian cancer cells and tested if blocking of PELP1 signaling axis will have any therapeutic effect. We have established OVCAR3, SKOV3 and ES2 model cells that stably express PELP1 specific shRNA and these model cells showed ∼80% decrease in PELP1 expression compared to vector transfected cells. PELP1 knock down significantly reduced proliferation of the model cells and also enhanced chemotherapy sensitivity of carboplatin and paclitaxel in ovarian cancer cells. Interestingly, PELP1 down regulated ovarian cancer cells showed cytoskeletal defects with low F-actin structures and increased accumulation of stress fibers. Boyden Chamber and wound healing assays revealed that PELP1 knockdown significantly affect the migratory potential of ovarian cancer cells. Microarray analysis of the model cells using metastasis pathway array revealed that PELP1 down regulation affects the expression of selective genes involved in metastasis including Myc, MTA1, MMP2 and MMP9. Zymography analysis confirmed that PELP1 knockdown caused a decrease in the activation of MMP2 and MMP9 in ovarian cancer cell lines. To examine the in vivo therapeutic potential, we examined whether systemically administered PELP1siRNA in a neurtal nanoliposomal formulation (DOPC) will reduce tumor growth using ovarian cancer xenograft model. Nude mice (n=10) injected with SKOV3ip1 ovarian cancer cells received therapy with either control siRNA-DOPC or PELP1siRNA-DOPC. Results showed that nude mice injected with PELP1-siRNA-DOPC have 54% less number of tumor nodules and exhibited 51% reduction in tumor growth and 84% reduction in ascites volume compared to control siRNA liposome injected mice. IHC examination of the tumors revealed that PELP1-siRNA liposome injected tumors showed low expression of PELP1, PCNA and MMP2. Collectively, these results suggest PELP1 signaling axis as a potential drugable target and PELP1siRNA liposomes could be used as a novel drug for therapeutic targeting of ovarian metastasis. The combination of targeting PELP1 along with the other chemotherapeutic drugs might be an effective new drug regimen for treatment of ovarian cancer progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3669.