Humpton, Timothy J, Alagesan, Brinda, DeNicola, Gina M, Lu, Dan, Yordanov, Georgi N, Leonhardt, Carl S, Yao, Melissa A, Alagesan, Priya, Zaatari, Maya N, Park, Youngkyu et al (show 7 more authors)
(2019)
Oncogenic KRAS Induces NIX-Mediated Mitophagy to Promote Pancreatic Cancer.
CANCER DISCOVERY, 9 (9).
pp. 1268-1287.
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Abstract
Activating <i>KRAS</i> mutations are found in nearly all cases of pancreatic ductal adenocarcinoma (PDAC), yet effective clinical targeting of oncogenic KRAS remains elusive. Understanding of KRAS-dependent PDAC-promoting pathways could lead to the identification of vulnerabilities and the development of new treatments. We show that oncogenic <i>KRAS</i> induces <i>BNIP3L</i>/NIX expression and a selective mitophagy program that restricts glucose flux to the mitochondria and enhances redox capacity. Loss of <i>Nix</i> restores functional mitochondria to cells, increasing demands for NADPH reducing power and decreasing proliferation in glucose-limited conditions. <i>Nix</i> deletion markedly delays progression of pancreatic cancer and improves survival in a murine (KPC) model of PDAC. Although conditional <i>Nix</i> ablation <i>in vivo</i> initially results in the accumulation of mitochondria, mitochondrial content eventually normalizes via increased mitochondrial clearance programs, and pancreatic intraepithelial neoplasia (PanIN) lesions progress to PDAC. We identify the KRAS-NIX mitophagy program as a novel driver of glycolysis, redox robustness, and disease progression in PDAC. SIGNIFICANCE: NIX-mediated mitophagy is a new oncogenic KRAS effector pathway that suppresses functional mitochondrial content to stimulate cell proliferation and augment redox homeostasis. This pathway promotes the progression of PanIN to PDAC and represents a new dependency in pancreatic cancer.<i>This article is highlighted in the In This Issue feature, p. 1143</i>.
| Item Type: | Article |
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| Uncontrolled Keywords: | Cell Line, Tumor, Mitochondria, Animals, Humans, Mice, Carcinoma, Pancreatic Ductal, Pancreatic Neoplasms, NADP, Membrane Proteins, Proto-Oncogene Proteins, Tumor Suppressor Proteins, Neoplasm Transplantation, Gene Expression Regulation, Neoplastic, Oxidation-Reduction, Glycolysis, Mutation, Proto-Oncogene Proteins p21(ras), Mitophagy |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 04 Jul 2019 14:50 |
| Last Modified: | 19 Jan 2023 00:38 |
| DOI: | 10.1158/2159-8290.CD-18-1409 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3048587 |
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