Isoprenylcysteine carboxylmethyltransferase deficiency exacerbates KRAS-driven pancreatic neoplasia via Notch suppression

Helen Court, Marc Amoyel, Michael Hackman, Kyoung Eun Lee, Ruliang Xu, George Miller, Dafna Bar-Sagi, Erika A Bach, Martin O Bergö, Mark R Philips

Research output: Contribution to journalArticle (Academic Journal)peer-review

30 Citations (Scopus)

Abstract

RAS is the most frequently mutated oncogene in human cancers. Despite decades of effort, anti-RAS therapies have remained elusive. Isoprenylcysteine carboxylmethyltransferase (ICMT) methylates RAS and other CaaX-containing proteins, but its potential as a target for cancer therapy has not been fully evaluated. We crossed a Pdx1-Cre;LSL-KrasG12D mouse, which is a model of pancreatic ductal adenocarcinoma (PDA), with a mouse harboring a floxed allele of Icmt. Surprisingly, we found that ICMT deficiency dramatically accelerated the development and progression of neoplasia. ICMT-deficient pancreatic ductal epithelial cells had a slight growth advantage and were resistant to premature senescence by a mechanism that involved suppression of cyclin-dependent kinase inhibitor 2A (p16INK4A) expression. ICMT deficiency precisely phenocopied Notch1 deficiency in the Pdx1-Cre;LSL-KrasG12D model by exacerbating pancreatic intraepithelial neoplasias, promoting facial papillomas, and derepressing Wnt signaling. Silencing ICMT in human osteosarcoma cells decreased Notch1 signaling in response to stimulation with cell-surface ligands. Additionally, targeted silencing of Ste14, the Drosophila homolog of Icmt, resulted in defects in wing development, consistent with Notch loss of function. Our data suggest that ICMT behaves like a tumor suppressor in PDA because it is required for Notch1 signaling.

Original languageEnglish
Pages (from-to)4681-94
Number of pages14
JournalJournal of Clinical Investigation
Volume123
Issue number11
DOIs
Publication statusPublished - Nov 2013

Keywords

  • Animals
  • Animals, Genetically Modified
  • Carcinoma in Situ
  • Carcinoma, Pancreatic Ductal
  • Cell Line, Tumor
  • Disease Models, Animal
  • Drosophila melanogaster
  • Female
  • Genes, ras
  • Humans
  • Male
  • Metaplasia
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Mutation
  • Pancreas
  • Pancreatic Neoplasms
  • Protein Methyltransferases
  • Receptor, Notch1
  • Signal Transduction

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