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 language | English (US) |
|---|---|
| Pages (from-to) | 2325-2336 |
| Number of pages | 12 |
| Journal | Cell Reports |
| Volume | 14 |
| Issue number | 10 |
| DOIs | |
| State | Published - Mar 15 2016 |
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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 journal › Article
}
TY - JOUR
T1 - Mutant KRas-Induced Mitochondrial Oxidative Stress in Acinar Cells Upregulates EGFR Signaling to Drive Formation of Pancreatic Precancerous Lesions
AU - Liou, Geou Yarh
AU - Döppler, Heike
AU - DelGiorno, Kathleen E.
AU - Zhang, Lizhi
AU - Leitges, Michael
AU - Crawford, Howard C.
AU - Murphy, Michael P.
AU - Storz, Peter
PY - 2016/3/15
Y1 - 2016/3/15
N2 - 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.
AB - 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.
KW - Growth factor signaling
KW - Kras
KW - Mitochondria
KW - Oxidative stress
KW - Pancreatic cancer
KW - PanIN
UR - http://www.scopus.com/inward/record.url?scp=84960339672&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84960339672&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2016.02.029
DO - 10.1016/j.celrep.2016.02.029
M3 - Article
C2 - 26947075
AN - SCOPUS:84960339672
VL - 14
SP - 2325
EP - 2336
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 10
ER -