Mutant KRas-Induced Mitochondrial Oxidative Stress in Acinar Cells Upregulates EGFR Signaling to Drive Formation of Pancreatic Precancerous Lesions
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 i...
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| Format: | Article |
| Language: | English |
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Elsevier
2016-03-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124716301322 |
| _version_ | 1828793420351537152 |
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| author | Geou-Yarh Liou Heike Döppler Kathleen E. DelGiorno Lizhi Zhang Michael Leitges Howard C. Crawford Michael P. Murphy Peter Storz |
| author_facet | Geou-Yarh Liou Heike Döppler Kathleen E. DelGiorno Lizhi Zhang Michael Leitges Howard C. Crawford Michael P. Murphy Peter Storz |
| author_sort | Geou-Yarh Liou |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T03:26:18Z |
| format | Article |
| id | doaj.art-1bbd910a58374db68c711128890e53bc |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-12T03:26:18Z |
| publishDate | 2016-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-1bbd910a58374db68c711128890e53bc2022-12-22T00:40:01ZengElsevierCell Reports2211-12472016-03-0114102325233610.1016/j.celrep.2016.02.029Mutant KRas-Induced Mitochondrial Oxidative Stress in Acinar Cells Upregulates EGFR Signaling to Drive Formation of Pancreatic Precancerous LesionsGeou-Yarh Liou0Heike Döppler1Kathleen E. DelGiorno2Lizhi Zhang3Michael Leitges4Howard C. Crawford5Michael P. Murphy6Peter Storz7Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USADepartment of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USADepartment of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USADepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USAThe Biotechnology Centre of Oslo, University of Oslo, 0349 Oslo, NorwayDepartment of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USAMRC Mitochondrial Biology Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UKDepartment of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USAThe 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.http://www.sciencedirect.com/science/article/pii/S2211124716301322pancreatic cancerPanINKrasoxidative stressmitochondriagrowth factor signaling |
| spellingShingle | Geou-Yarh Liou Heike Döppler Kathleen E. DelGiorno Lizhi Zhang Michael Leitges Howard C. Crawford Michael P. Murphy Peter Storz Mutant KRas-Induced Mitochondrial Oxidative Stress in Acinar Cells Upregulates EGFR Signaling to Drive Formation of Pancreatic Precancerous Lesions Cell Reports pancreatic cancer PanIN Kras oxidative stress mitochondria growth factor signaling |
| title | Mutant KRas-Induced Mitochondrial Oxidative Stress in Acinar Cells Upregulates EGFR Signaling to Drive Formation of Pancreatic Precancerous Lesions |
| title_full | Mutant KRas-Induced Mitochondrial Oxidative Stress in Acinar Cells Upregulates EGFR Signaling to Drive Formation of Pancreatic Precancerous Lesions |
| title_fullStr | Mutant KRas-Induced Mitochondrial Oxidative Stress in Acinar Cells Upregulates EGFR Signaling to Drive Formation of Pancreatic Precancerous Lesions |
| title_full_unstemmed | Mutant KRas-Induced Mitochondrial Oxidative Stress in Acinar Cells Upregulates EGFR Signaling to Drive Formation of Pancreatic Precancerous Lesions |
| title_short | Mutant KRas-Induced Mitochondrial Oxidative Stress in Acinar Cells Upregulates EGFR Signaling to Drive Formation of Pancreatic Precancerous Lesions |
| title_sort | mutant kras induced mitochondrial oxidative stress in acinar cells upregulates egfr signaling to drive formation of pancreatic precancerous lesions |
| topic | pancreatic cancer PanIN Kras oxidative stress mitochondria growth factor signaling |
| url | http://www.sciencedirect.com/science/article/pii/S2211124716301322 |
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