Abstract 1154: Targeted silencing of elongation factor 2 kinase (EF2K) suppresses invasion, cell proliferation and growth in an orthotopic model of ovarian cancer
Authors: Mumin Alper Erdogan, Bulent Ozpolat
Journal: Cancer Research (2017)

Abstract Ovarian cancer (OCa) is one of the most aggressive and deadliest cancer and is currently incurable disease with the poorest prognosis and survival rates (4%, 5year survival rates). One of the hallmarks of OCa is its early invasion and metastasis, resistance to chemotherapeutics and radiotherapy and aggressive tumor progression. These features contribute to a poor prognosis of this highly complex malignancy with many molecular alterations and mutations involving multiple genes. The major reason for patient death is due to metastasis and resistance to current therapies that include chemotherapy, hormonal therapy and radiation. Therefore, novel molecular targets and therapeutics strategies are urgently needed to enhance the efficacy of current therapies and prolong patient survival. Recently, we discovered that Eukaryotic elongation factor-2 kinase (EF2K), an atypical kinase, is dramatically up-regulated in cells and promotes cell survival and proliferation, its inhibition significantly reduces cell growth and colony formation. However, the role that EF2K in OCa and pathways regulating cell proliferation, colony formation, survival, invasion/metastasis and resistance remains is largely unknown. Here, we show that specific inhibition of EF2K by siRNA-mediated knockdown markedly inhibits OCa (HeyA8 and SKOV3ip1) cell proliferation, colony formation and invasion/migration in vitro. This targeting resulted in a substantial decrease in eEF2 phosphorylation in the tumors, and led to the inhibition of tumor growth and metastasis. Lack of function demonstrated that EF2K regulates Beta1-integrin, p-SRC, p-FAK, p-AKT, p-IF2alpha, p-ERK expression. Our western blot data suggested that EF2K may enhance tumorigenesis and metastasis through the upregulation of pro-tumorigenic, metastatic proteins and pathways in OCa. Furthermore, we found that therapeutic inhibition of EF2K by systemically administered (i.v) nanoliposomal EF2K siRNA inhibited growth SKOV3 tumor xenografts and intraperitoneal tumor nodules (intraperitoneal metastatic model) in nude mice (p&amp;lt;0.05), demonstrating the role of EF2K in tumorigenesis and metastatic phenotype. We also found that treatment with EF2K siRNA resulted in significant decrease in mean tumor weight, induced apoptosis (as judged by a positive TUNEL assay) and the downregulation of the proliferative marker Ki-67. Collectively, our data suggest, for the first time, the pivotal role of eEF2K in OCa cell proliferation, invasion and tumor progression and establish eEF2K as a novel potential therapeutic target in highly aggressive and lethal ovarian cancer. Citation Format: Mumin Alper Erdogan, Bulent Ozpolat. Targeted silencing of elongation factor 2 kinase (EF2K) suppresses invasion, cell proliferation and growth in an orthotopic model of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1154. doi:10.1158/1538-7445.AM2017-1154