Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA.
Nature. 2018 Nov;563(7732):569-573. doi: 10.1038/s41586-018-0697-7. Epub 2018 Nov 14.
Autophagy captures intracellular components and delivers them to lysosomes, where they are degraded and recycled to sustain metabolism and to enable survival during starvation. Acute, whole-body deletion of the essential autophagy gene Atg7 in adult mice causes a systemic metabolic defect that manifests as starvation intolerance and gradual loss of white adipose tissue, liver glycogen and muscle mass. Cancer cells also benefit from autophagy. Deletion of essential autophagy genes impairs the metabolism, proliferation, survival and malignancy of spontaneous tumours in models of autochthonous cancer. Acute, systemic deletion of Atg7 or acute, systemic expression of a dominant-negative ATG4b in mice induces greater regression of KRAS-driven cancers than does tumour-specific autophagy deletion, which suggests that host autophagy promotes tumour growth. Here we show that host-specific deletion of Atg7 impairs the growth of multiple allografted tumours, although not all tumour lines were sensitive to host autophagy status. Loss of autophagy in the host was associated with a reduction in circulating arginine, and the sensitive tumour cell lines were arginine auxotrophs owing to the lack of expression of the enzyme argininosuccinate synthase 1. Serum proteomic analysis identified the arginine-degrading enzyme arginase I (ARG1) in the circulation of Atg7-deficient hosts, and in vivo arginine metabolic tracing demonstrated that serum arginine was degraded to ornithine. ARG1 is predominantly expressed in the liver and can be released from hepatocytes into the circulation. Liver-specific deletion of Atg7 produced circulating ARG1, and reduced both serum arginine and tumour growth. Deletion of Atg5 in the host similarly regulated [corrected] circulating arginine and suppressed tumorigenesis, which demonstrates that this phenotype is specific to autophagy function rather than to deletion of Atg7. Dietary supplementation of Atg7-deficient hosts with arginine partially restored levels of circulating arginine and tumour growth. Thus, defective autophagy in the host leads to the release of ARG1 from the liver and the degradation of circulating arginine, which is essential for tumour growth; this identifies a metabolic vulnerability of cancer.
自噬捕获细胞内成分，并将其递送至溶酶体，在溶酶体中被降解并回收，以维持代谢并在饥饿时促进存活。在成年小鼠中急性、全身性敲除必需自噬基因 Atg7 会导致全身性代谢缺陷，表现为不耐受饥饿和逐渐丧失白色脂肪组织、肝糖原和肌肉质量。癌细胞也受益于自噬。在同源性癌症模型中，敲除必需的自噬基因会损害代谢、增殖、存活和自发性肿瘤的恶性程度。在小鼠中，急性、全身性敲除 Atg7 或急性、全身性表达显性失活型 ATG4b 会诱导 KRAS 驱动的癌症更大程度的消退，而非肿瘤特异性自噬缺失，这表明宿主自噬促进肿瘤生长。本文中我们表明，宿主特异性敲除 Atg7 会损害多种同种异体移植瘤的生长，尽管并非所有肿瘤系都对宿主自噬状态敏感。宿主自噬缺失与循环精氨酸减少有关，而敏感的肿瘤细胞系由于缺乏酶精氨酸代琥珀酸合酶 1 的表达而成为精氨酸营养缺陷型。血清蛋白质组学分析鉴定出循环中的精氨酸降解酶精氨酸酶 I（ARG1），在 Atg7 缺失宿主的体内精氨酸代谢追踪中证明血清精氨酸被降解为鸟氨酸。ARG1 主要在肝脏中表达，并且可以从肝细胞释放到循环中。肝脏特异性敲除 Atg7 会产生循环中的 ARG1，并降低血清精氨酸和肿瘤生长。宿主中 Atg5 的缺失同样调节了循环中的精氨酸并抑制了肿瘤发生，这表明这种表型是自噬功能特有的，而不是 Atg7 的缺失。用精氨酸补充 Atg7 缺失的宿主部分恢复了循环精氨酸和肿瘤生长水平。因此，宿主中缺陷的自噬导致 ARG1 从肝脏中释放并降解循环中的精氨酸，这对肿瘤生长至关重要；这确定了癌症的代谢脆弱性。
