Abstract 2642: EF2-kinase (EF2K): A novel molecular target in ovarian and pancreatic cancers (2015)

Abstract Ovarian cancer (OC) and Pancreatic ductal adenocarcinoma (PDAC) are the most aggressive and deadliest cancers and is currently incurable disease with the poorest prognosis and survival rates (4% and 30% 5-year survival rates, respectively). The poor prognosis is attributed to the extensive local tumor invasion and the resistance to existing cancer therapeutics, which are the major characteristics of both cancers and the impediment to effective cure this lethal diseases. Although both cancers have a well-defined spectrum of highly recurrent oncogenic lesions, including p53, c-myc, K-ras, CDKN2A /p16, TP53 and SMAD4/DPC4 effective therapies have not yet been developed. Therefore, novel molecular targets and therapeutics strategies are urgently needed. 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 these cancers and pathways regulating survival, invasion/metastasis and resistance remains is largely unknown. Here, we show that specific inhibition of EF2K by siRNA-mediated knock markedly inhibits OC (HeyA8 and SKOV3ip1) and PDAC (PANC1 and MiaPaca-2) invasion in in vitro matrigel assay. Furthermore, inhibit EF2K expression, also significantly reduced tissue transglutaminase (TG2), a multifunctional enzyme implicated in regulation of cell survival, migration and invasion and beta-integrin. We found that eEF-2K regulates TG2, at the transcription level, as evidenced by eEF-2K knockdown-mediated marked down-regulation of TG2 protein and mRNA levels by Western blot and RT-PCR, respectively. Lack of function and overexpression (by Lenti-based system) demonstrated that EF2K regulates TG2,Beta-1 integrin, uPAR MMP-2, p-SRC expression. In addition, we found down-regulation of EF2K or TG2 by siRNA suppresses the downstream key cellular pathways supporting invasion, including epithelial-mesenchymal transition (EMT) through the modulation of the zinc finger transcription factors, belonging to ZEB1 family, and the tight junction proteins, claudins. Furthermore, we found that therapeutic inhibition of EF2K by systemically administered (i.v) nano liposomal EF2K siRNA inhibited growth SKOV3and intraperitoneal tumor nodules (intraperitoneal metastatic model) Panc1 tumor xenografts in nude mice (p&lt;0.05), demonstrating the role of EF2K in tumorigenesis and metastatic phenotype. Collectively, our data suggest, for the first time, the pivotal role of eEF-2K in PDAC and OC invasion and tumor progression and establish eEF-2K as a novel potential novel therapeutic target in both highly aggressive and lethal cancers. Citation Format: Ahmed Ashour, Alper Erdogan, Sultan Neslihan Alpay, Nermin Kahraman, Erkan Yuka, Gabriel Lopez-Berestein, Bulent Ozpolat. EF2-kinase (EF2K): A novel molecular target in ovarian and pancreatic cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2642. doi:10.1158/1538-7445.AM2015-2642