Oncogenic KRAS Induces NIX-Mediated Mitophagy to Promote Pancreatic Cancer
Oncogenic KRAS Induces NIX-Mediated Mitophagy to Promote Pancreatic Cancer
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DOI：
10.1158/2159-8290.cd-18-1409
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发表时间：
2019-09-01
期刊：
影响因子：
28.2
通讯作者：
Tuveson, David A.
中科院分区：
文献类型：
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作者：
Humpton, Timothy J.;Alagesan, Brinda;Tuveson, David A.
几乎所有胰腺导管腺癌 (PDAC) 病例中都发现激活 KRAS 突变，但致癌 KRAS 的有效临床靶向仍然难以捉摸。了解 KRAS 依赖的 PDAC 促进途径可能有助于识别脆弱性并开发新的治疗方法。我们发现致癌 KRAS 诱导 BNIP3L/NIX 表达和选择性线粒体自噬程序，限制葡萄糖流向线粒体并增强氧化还原能力。 Nix 的缺失可以恢复细胞的功能性线粒体，增加对 NADPH 的需求，从而降低能量并减少葡萄糖限制条件下的增殖。 Nix 缺失可显着延缓胰腺癌的进展并提高 PDAC 小鼠 (KPC) 模型的生存率。尽管体内条件性 Nix 消融最初会导致线粒体积累，但线粒体含量最终通过增加线粒体清除程序而恢复正常，并且胰腺上皮内瘤变 (PanIN) 病变进展为 PDAC。我们将 KRAS-NIX 线粒体自噬程序确定为 PDAC 中糖酵解、氧化还原稳健性和疾病进展的新驱动因素。意义：NIX 介导的线粒体自噬是一种新的致癌 KRAS 效应途径，可抑制功能性线粒体内容物，从而刺激细胞增殖并增强氧化还原稳态。该通路促进 PanIN 向 PDAC 的进展，代表了胰腺癌的新依赖性。
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.