Oncogenic KRAS Induces NIX-Mediated Mitophagy to Promote Pancreatic Cancer.

Autor:	Humpton TJ; Cancer Research UK Beatson Institute, Glasgow, United Kingdom., Alagesan B; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York.; Medical Scientist Training Program, Stony Brook University, Stony Brook, New York., DeNicola GM; Department of Cancer Physiology, Moffitt Cancer Center and Research Institute, Tampa, Florida., Lu D; Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom., Yordanov GN; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York., Leonhardt CS; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York., Yao MA; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York., Alagesan P; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York., Zaatari MN; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York., Park Y; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York., Skepper JN; Cambridge Advanced Imaging Centre, Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, United Kingdom., Macleod KF; The Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois., Perez-Mancera PA; Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom., Murphy MP; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, United Kingdom., Evan GI; Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom., Vousden KH; The Francis Crick Institute, London, United Kingdom., Tuveson DA; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. Dtuveson@cshl.edu.; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2019 Sep; Vol. 9 (9), pp. 1268-1287. Date of Electronic Publication: 2019 Jul 01.
DOI:	10.1158/2159-8290.CD-18-1409
Abstrakt:	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.)
Databáze:	MEDLINE
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