Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis
Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis
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DOI：
10.1101/gad.219642.113
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发表时间：
2013-07-01
影响因子：
10.5
通讯作者：
White, Eileen
中科院分区：
文献类型：
--
作者：
Guo, Jessie Yanxiang;Karsli-Uzunbas, Gizem;White, Eileen
大自噬（自噬）降解和消化蛋白质和细胞器，以支持新陈代谢和饥饿中的生存。致癌Ras上调自噬，Ras转化的细胞系需要自噬来实现线粒体功能、应激存活和移植肿瘤生长。在这里，在非小细胞肺癌（NSCLC）小鼠模型中，基本的自噬基因自噬相关7（atg 7）与K-ras（G12 D）激活同时被删除。缺乏ATG 7的肿瘤积累了功能失调的线粒体，并过早地诱导了p53和增殖停滞，这降低了肿瘤负荷，而p53缺失部分减轻了肿瘤负荷。ATG 7缺失改变了肿瘤的命运，从腺瘤和癌到嗜酸细胞瘤--罕见的、主要是良性的肿瘤，其特征在于有缺陷的线粒体的积累。令人惊讶的是，只有当p53缺失时，atg 7缺陷型肿瘤才会发生脂质积聚。atg 7-和p53-缺陷的肿瘤衍生细胞系（TDCL）的饥饿存活率降低，并形成胞囊而不是肿瘤，表明脂质储存的利用缺陷。atg 7缺陷减少了脂肪酸氧化（FAO）并增加了对FAO抑制的敏感性，表明随着p53丢失，Ras驱动的肿瘤需要线粒体功能和脂质催化剂的自噬。因此，自噬是肿瘤发生所必需的，自噬缺陷可能是嗜酸细胞瘤发生的分子基础。此外，癌症需要自噬在癌基因和肿瘤抑制基因特异性的代谢中发挥不同的作用。
Macroautophagy (autophagy hereafter) degrades and recycles proteins and organelles to support metabolism and survival in starvation. Oncogenic Ras up-regulates autophagy, and Ras-transformed cell lines require autophagy for mitochondrial function, stress survival, and engrafted tumor growth. Here, the essential autophagy gene autophagy-related-7 (atg7) was deleted concurrently with K-ras(G12D) activation in mouse models for non-small-cell lung cancer (NSCLC). atg7-deficient tumors accumulated dysfunctional mitochondria and prematurely induced p53 and proliferative arrest, which reduced tumor burden that was partly relieved by p53 deletion. atg7 loss altered tumor fate from adenomas and carcinomas to oncocytomas-rare, predominantly benign tumors characterized by the accumulation of defective mitochondria. Surprisingly, lipid accumulation occurred in atg7-deficient tumors only when p53 was deleted. atg7-and p53-deficient tumor-derived cell lines (TDCLs) had compromised starvation survival and formed lipidic cysts instead of tumors, suggesting defective utilization of lipid stores. atg7 deficiency reduced fatty acid oxidation (FAO) and increased sensitivity to FAO inhibition, indicating that with p53 loss, Ras-driven tumors require autophagy for mitochondrial function and lipid catabolism. Thus, autophagy is required for carcinoma fate, and autophagy defects may be a molecular basis for the occurrence of oncocytomas. Moreover, cancers require autophagy for distinct roles in metabolism that are oncogene-and tumor suppressor gene-specific.