1. Oncogenic KRAS Induces NIX-Mediated Mitophagy to Promote Pancreatic Cancer.
- Author
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Humpton TJ, Alagesan B, DeNicola GM, Lu D, Yordanov GN, Leonhardt CS, Yao MA, Alagesan P, Zaatari MN, Park Y, Skepper JN, Macleod KF, Perez-Mancera PA, Murphy MP, Evan GI, Vousden KH, and Tuveson DA
- Subjects
- Animals, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal metabolism, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Glycolysis, Humans, Membrane Proteins genetics, Mice, Mitophagy, Mutation, NADP metabolism, Neoplasm Transplantation, Oxidation-Reduction, Pancreatic Neoplasms genetics, Pancreatic Neoplasms metabolism, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins p21(ras) metabolism, Tumor Suppressor Proteins genetics, Carcinoma, Pancreatic Ductal pathology, Membrane Proteins metabolism, Mitochondria metabolism, Pancreatic Neoplasms pathology, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins p21(ras) genetics, Tumor Suppressor Proteins metabolism
- Abstract
Activating KRAS 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 KRAS induces BNIP3L /NIX expression and a selective mitophagy program that restricts glucose flux to the mitochondria and enhances redox capacity. Loss of Nix restores functional mitochondria to cells, increasing demands for NADPH reducing power and decreasing proliferation in glucose-limited conditions. Nix deletion markedly delays progression of pancreatic cancer and improves survival in a murine (KPC) model of PDAC. Although conditional Nix ablation in vivo 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. This article is highlighted in the In This Issue feature, p. 1143 ., (©2019 American Association for Cancer Research.)
- Published
- 2019
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