Autophagy is required for glucose homeostasis and lung tumor maintenance.
Autophagy is required for glucose homeostasis and lung tumor maintenance.
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DOI：
10.1158/2159-8290.cd-14-0363
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发表时间：
2014-08
期刊：
影响因子：
28.2
通讯作者：
White E
中科院分区：
文献类型：
--
作者：
Karsli-Uzunbas G;Guo JY;Price S;Teng X;Laddha SV;Khor S;Kalaany NY;Jacks T;Chan CS;Rabinowitz JD;White E
大自噬（下文称为自噬）使细胞内组分活化以维持线粒体代谢，线粒体代谢促进肺癌的生长、应激耐受和恶性，这表明自噬抑制可能具有抗肿瘤活性。为了评估自噬在正常和肿瘤组织中的功能意义，我们在整个成年小鼠中有条件地删除了必需的自噬基因，自噬相关基因7，Atg 7。在这里，我们报告了全身性ATG 7消融导致感染和神经退行性变的易感性，将生存期限制在2-3个月。此外，在禁食时，自噬缺陷小鼠遭受致命的低血糖。先前的自噬消融并没有改变通过激活致癌KrasG 12 D和缺失Trp 53肿瘤抑制因子而引发的非小细胞肺癌（NSCLC）的效率。然而，在患有既存NSCLC的小鼠中进行急性自噬消融可阻断肿瘤生长，促进肿瘤细胞死亡，并产生更多良性疾病（嗜酸细胞瘤）。这种抗肿瘤活性发生在破坏正常组织之前，表明急性自噬抑制可能在癌症中具有治疗益处。
Macroautophagy (autophagy hereafter) recycles intracellular components to sustain mitochondrial metabolism that promotes the growth, stress tolerance and malignancy of lung cancers, suggesting that autophagy inhibition may have antitumor activity. To assess the functional significance of autophagy in both normal and tumor tissue, we conditionally deleted the essential autophagy gene, autophagy-related-7, Atg7, throughout adult mice. Here we report that systemic ATG7 ablation caused susceptibility to infection and neurodegeneration that limited survival to 2–3 months. Moreover, upon fasting, autophagy-deficient mice suffered fatal hypoglycemia. Prior autophagy ablation did not alter the efficiency of non-small-cell lung cancer (NSCLC) initiation by activation of oncogenic KrasG12D and deletion of the Trp53 tumor suppressor. Acute autophagy ablation in mice with pre-existing NSCLC, however, blocked tumor growth, promoted tumor cell death, and generated more benign disease (oncocytomas). This anti-tumor activity occurred prior to destruction of normal tissues, suggesting that, acute autophagy inhibition may be therapeutically beneficial in cancer.