Mutant KRas-Induced Mitochondrial Oxidative Stress in Acinar Cells Upregulates EGFR Signaling to Drive Formation of Pancreatic Precancerous Lesions

Geou Yarh Liou, Heike Döppler, Kathleen E. DelGiorno, Lizhi Zhang, Michael Leitges, Howard C. Crawford, Michael P. Murphy, Peter Storz

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

The development of pancreatic cancer requires the acquisition of oncogenic KRas mutations and upregulation of growth factor signaling, but the relationship between these is not well established. Here, we show that mutant KRas alters mitochondrial metabolism in pancreatic acinar cells, resulting in increased generation of mitochondrial reactive oxygen species (mROS). Mitochondrial ROS then drives the dedifferentiation of acinar cells to a duct-like progenitor phenotype and progression to PanIN. This is mediated via the ROS-receptive kinase protein kinase D1 and the transcription factors NF-κB1 and NF-κB2, which upregulate expression of the epidermal growth factor, its ligands, and their sheddase ADAM17. In vivo, interception of KRas-mediated generation of mROS reduced the formation of pre-neoplastic lesions. Hence, our data provide insight into how oncogenic KRas interacts with growth factor signaling to induce the formation of pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)2325-2336
Number of pages12
JournalCell Reports
Volume14
Issue number10
DOIs
StatePublished - Mar 15 2016

Fingerprint

Oxidative stress
Acinar Cells
Pancreatic Neoplasms
Reactive Oxygen Species
Intercellular Signaling Peptides and Proteins
Oxidative Stress
Up-Regulation
Epidermal Growth Factor
Metabolism
Ducts
Protein Kinases
Transcription Factors
Phosphotransferases
Ligands
Phenotype
Mutation
human TFB1M protein
ADAM17 Protein

Keywords

  • Growth factor signaling
  • Kras
  • Mitochondria
  • Oxidative stress
  • Pancreatic cancer
  • PanIN

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Mutant KRas-Induced Mitochondrial Oxidative Stress in Acinar Cells Upregulates EGFR Signaling to Drive Formation of Pancreatic Precancerous Lesions. / Liou, Geou Yarh; Döppler, Heike; DelGiorno, Kathleen E.; Zhang, Lizhi; Leitges, Michael; Crawford, Howard C.; Murphy, Michael P.; Storz, Peter.

In: Cell Reports, Vol. 14, No. 10, 15.03.2016, p. 2325-2336.

Research output: Contribution to journalArticle

Liou, Geou Yarh ; Döppler, Heike ; DelGiorno, Kathleen E. ; Zhang, Lizhi ; Leitges, Michael ; Crawford, Howard C. ; Murphy, Michael P. ; Storz, Peter. / Mutant KRas-Induced Mitochondrial Oxidative Stress in Acinar Cells Upregulates EGFR Signaling to Drive Formation of Pancreatic Precancerous Lesions. In: Cell Reports. 2016 ; Vol. 14, No. 10. pp. 2325-2336.
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