Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Genes Dev. 2011 Apr 1;25(7):717-29. doi: 10.1101/gad.2016111. Epub 2011 Mar 15.
Macroautophagy (autophagy) is a regulated catabolic pathway to degrade cellular organelles and macromolecules. The role of autophagy in cancer is complex and may differ depending on tumor type or context. Here we show that pancreatic cancers have a distinct dependence on autophagy. Pancreatic cancer primary tumors and cell lines show elevated autophagy under basal conditions. Genetic or pharmacologic inhibition of autophagy leads to increased reactive oxygen species, elevated DNA damage, and a metabolic defect leading to decreased mitochondrial oxidative phosphorylation. Together, these ultimately result in significant growth suppression of pancreatic cancer cells in vitro. Most importantly, inhibition of autophagy by genetic means or chloroquine treatment leads to robust tumor regression and prolonged survival in pancreatic cancer xenografts and genetic mouse models. These results suggest that, unlike in other cancers where autophagy inhibition may synergize with chemotherapy or targeted agents by preventing the up-regulation of autophagy as a reactive survival mechanism, autophagy is actually required for tumorigenic growth of pancreatic cancers de novo, and drugs that inactivate this process may have a unique clinical utility in treating pancreatic cancers and other malignancies with a similar dependence on autophagy. As chloroquine and its derivatives are potent inhibitors of autophagy and have been used safely in human patients for decades for a variety of purposes, these results are immediately translatable to the treatment of pancreatic cancer patients, and provide a much needed, novel vantage point of attack.
自噬（自噬作用）是一种调节性的分解代谢途径，可降解细胞细胞器和大分子。自噬在癌症中的作用较为复杂，可能因肿瘤类型或背景而异。在此我们表明，胰腺癌具有明显的自噬依赖性。在基础条件下，胰腺癌原发肿瘤和细胞系表现出升高的自噬活性。自噬的遗传或药理学抑制会导致活性氧增加、DNA 损伤增加以及代谢缺陷，导致线粒体氧化磷酸化减少。所有这些最终导致体外胰腺癌细胞的显著生长抑制。最重要的是，通过遗传手段或氯喹治疗抑制自噬会导致胰腺癌细胞异种移植和遗传小鼠模型中的肿瘤明显消退和生存时间延长。这些结果表明，与其他癌症不同，自噬抑制可能通过阻止自噬作为反应性生存机制的上调与化疗或靶向药物协同作用，自噬实际上是新发生的胰腺癌肿瘤发生所必需的，而使该过程失活的药物可能在治疗胰腺癌和其他依赖自噬的恶性肿瘤方面具有独特的临床应用价值。由于氯喹及其衍生物是自噬的有效抑制剂，并且几十年来已安全地用于人类患者，用于多种用途，因此这些结果可立即转化为治疗胰腺癌患者，为其提供急需的、新颖的攻击角度。
