Oncogenic KRAS Induces NIX-Mediated Mitophagy to Promote Pancreatic Cancer

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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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
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