title: A hypusine-eIF5A-PEAK1 switch regulates the pathogenesis of pancreatic cancer.
abstract: Deregulation of protein synthesis is a hallmark of cancer cell proliferation, survival, and metastatic progression. eIF5A1 and its highly related isoform eIF5A2 are translation initiation factors that have been implicated in a range of human malignancies, but how they control cancer development and disease progression is still poorly understood. Here, we investigated how eIF5A proteins regulate pancreatic ductal adenocarcinoma (PDAC) pathogenesis. eIF5A proteins are the only known proteins regulated by a distinct posttranslational modification termed hypusination, which is catalyzed by two enzymes, deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). The highly selective nature of the hypusine modification and its amenability to pharmacologic inhibition make eIF5A proteins attractive therapeutic targets. We found that the expression and hypusination of eIF5A proteins are upregulated in human PDAC tissues and in premalignant pancreatic intraepithelial neoplasia tissues isolated from Pdx-1-Cre: LSL-KRAS(G12D) mice. Knockdown of eIF5A proteins in PDAC cells inhibited their growth in vitro and orthotopic tumor growth in vivo, whereas amplification of eIF5A proteins increased PDAC cell growth and tumor formation in mice. Small-molecule inhibitors of DHPS and DOHH both suppressed eIF5A hypusination, preventing PDAC cell growth. Interestingly, we found that eIF5A proteins regulate PDAC cell growth by modulating the expression of PEAK1, a nonreceptor tyrosine kinase essential for PDAC cell growth and therapy resistance. Our findings suggest that eIF5A proteins utilize PEAK1 as a downstream effector to drive PDAC pathogenesis and that pharmacologic inhibition of the eIF5A-hypusine-PEAK1 axis may provide a novel therapeutic strategy to combat this deadly disease.
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, California. Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Ken
authors.initials: K
authors.lastname: Fujimura
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, California. Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Tracy
authors.initials: T
authors.lastname: Wright
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, California. Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Jan
authors.initials: J
authors.lastname: Strnadel
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Sharmeela
authors.initials: S
authors.lastname: Kaushal
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California. Division of Surgical Oncology, Department of Surgery, University of California, San Diego, La Jolla, California.
authors.forename: Cristina
authors.initials: C
authors.lastname: Metildi
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California. Division of Surgical Oncology, Department of Surgery, University of California, San Diego, La Jolla, California.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lowy
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California. Division of Surgical Oncology, Department of Surgery, University of California, San Diego, La Jolla, California.
authors.forename: Michael
authors.initials: M
authors.lastname: Bouvet
authors.affiliation: Department of Biology, California State University, Northridge, California.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Kelber
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, California. Moores Cancer Center, University of California, San Diego, La Jolla, California. rklemke@ucsd.edu.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Klemke
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000209:etiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000077768:Ciclopirox; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives* / Q000502:physiology; D051379:Mice; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000209:etiology*; D010448:Peptide Initiation Factors / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras); D011728:Pyridones / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000502:physiology*; D018631:ras Proteins / Q000502:physiology; D000093542:Gemcitabine; D000097574:Eukaryotic Translation Initiation Factor 5A
chemical_list: D000077768:Ciclopirox; D003841:Deoxycytidine; D008239:Lysine; D010448:Peptide Initiation Factors; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D011728:Pyridones; D016601:RNA-Binding Proteins; D018631:ras Proteins; D000093542:Gemcitabine; D000097574:Eukaryotic Translation Initiation Factor 5A; C117307:KRAS protein, human; C100028:hypusine; C573947:PEAK1 protein, human