Abstract LB-303: A hypusine-eIF5A-PEAK1 switch regulates the pathogenesis of pancreatic ductal adenocarcinoma

Abstract

Abstract Deregulation of mRNA translation and protein synthesis is a hallmark of cancer cell proliferation, survival, and metastatic progression. eIF5A1, and its highly related isoform eIF5A2, are critical translation initiation factors implicated in several human malignancies. Interestingly, eIF5A proteins are the only known proteins in nature that are regulated by a distinct posttranslational modification termed hypusination. This unique lysine modification ([N-(4-amino-2-hydroxybutyl)lysine]) involves polyamine biosynthesis and is catalyzed by two enzymes, deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). The highly selective nature of the hypusine modification and its amenability to pharmacological and genetic inhibition make the eIF5A-hypusine pathway an attractive therapeutic target to combat human cancers. Here, we investigated the role of eIF5A1/A2-hypusine pathway in pancreatic ductal adenocarcinoma (PDAC) pathogenesis. Hypusinated eIF5A1/A2 are upregulated in human PDAC tissues and in early stage PanIN tissues isolated from genetically engineered Pdx-Cre:LSL-KRASG12D mice. RNAi-mediated knockdown of eIF5A1/A2 in human PDAC cell lines inhibited cancer cell growth in vitro and inhibited tumor growth orthotopically in mice. In contrast, amplification of eIF5A1/A2 in PDAC cells increased orthotopic growth and tumor formation in mice. The deoxyhypusine hydroxylase inhibitor, CPX, and the deoxyhypusine synthase inhibitor, GC7, inhibited eIF5A1/A2 hypusination, preventing PDAC cell growth. Interestingly, we find that eIF5A1/A2 regulates cancer cell expansion by modulating the expression level of PEAK1, a non-receptor tyrosine kinase essential for PDAC cell growth. Our findings suggest that eIF5A1/A2 utilizes PEAK1 tyrosine kinase as a downstream effector to drive PDAC pathogenesis, and that pharmacological inhibition of the eIF5A1/A2 hypusination-PEAK1 axis may provide a novel therapeutic strategy to combat this deadly disease. Citation Format: Ken Fujimura, Tracy Wright, Jan Strnadel, Jonathan Kelber, Sharmeela Kaushal, Cristina Metildi, Andrew Lowy, Michael Bouvet, Richard Klemke. A hypusine-eIF5A-PEAK1 switch regulates the pathogenesis of pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-303. doi:10.1158/1538-7445.AM2014-LB-303