Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210000, China.
Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210000, China.
Cancer Cell. 2021 May 10;39(5):678-693.e11. doi: 10.1016/j.ccell.2021.02.016. Epub 2021 Mar 18.
Many cancers, including pancreatic ductal adenocarcinoma (PDAC), depend on autophagy-mediated scavenging and recycling of intracellular macromolecules, suggesting that autophagy blockade should cause tumor starvation and regression. However, until now autophagy-inhibiting monotherapies have not demonstrated potent anti-cancer activity. We now show that autophagy blockade prompts established PDAC to upregulate and utilize an alternative nutrient procurement pathway: macropinocytosis (MP) that allows tumor cells to extract nutrients from extracellular sources and use them for energy generation. The autophagy to MP switch, which may be evolutionarily conserved and not cancer cell restricted, depends on activation of transcription factor NRF2 by the autophagy adaptor p62/SQSTM1. NRF2 activation by oncogenic mutations, hypoxia, and oxidative stress also results in MP upregulation. Inhibition of MP in autophagy-compromised PDAC elicits dramatic metabolic decline and regression of transplanted and autochthonous tumors, suggesting the therapeutic promise of combining autophagy and MP inhibitors in the clinic.
许多癌症，包括胰腺导管腺癌（PDAC），依赖于自噬介导的细胞内大分子的清除和再循环，这表明自噬阻断应该会导致肿瘤饥饿和消退。然而，直到现在，抑制自噬的单一疗法并没有显示出强大的抗癌活性。我们现在表明，自噬阻断促使已建立的 PDAC 上调并利用替代的营养采购途径：巨胞饮（MP），使肿瘤细胞能够从细胞外来源提取营养物质并将其用于能量生成。这种自噬到 MP 的转变，可能是进化保守的，而不仅仅局限于癌细胞，依赖于自噬衔接蛋白 p62/SQSTM1 激活转录因子 NRF2。致癌突变、缺氧和氧化应激也会导致 MP 的上调。在自噬受损的 PDAC 中抑制 MP 会引起代谢急剧下降和移植和自发肿瘤的消退，这表明在临床上联合使用自噬和 MP 抑制剂具有治疗潜力。
