生物
癌变
胰腺癌
品脱1
癌症研究
去铁胺
炎症体
粒体自噬
线粒体
细胞生物学
癌症
自噬
细胞凋亡
免疫学
遗传学
炎症
生物化学
作者
Changfeng Li,Ying Zhang,Xing Cheng,Hua Yuan,Shan Zhu,Jiao Liu,Qirong Wen,Yangchun Xie,Jinbao Liu,Guido Kroemer,Daniel J. Klionsky,Michael T. Lotze,Herbert J. Zeh,Rui Kang,Daolin Tang
标识
DOI:10.1016/j.devcel.2018.07.012
摘要
Pancreatic cancer is an aggressive malignancy with changes in the tumor microenvironment. Here, we demonstrate that PINK1 and PARK2 suppressed pancreatic tumorigenesis through control of mitochondrial iron-dependent immunometabolism. Using mouse models of spontaneous pancreatic cancer, we show that depletion of Pink1 and Park2 accelerates mutant Kras-driven pancreatic tumorigenesis. PINK1-PARK2 pathway-mediated degradation of SLC25A37 and SLC25A28 increases mitochondrial iron accumulation, which leads to the HIF1A-dependent Warburg effect and AIM2-dependent inflammasome activation in tumor cells. AIM2-mediated HMGB1 release further induces expression of CD274/PD-L1. Consequently, pharmacological administration of mitochondrial iron chelator, anti-HMGB1 antibody, or genetic depletion of Hif1a or Aim2 in pink1−/− and park2−/− mice confers protection against pancreatic tumorigenesis. Low PARK2 expression and high SLC25A37 and AIM2 expression are associated with poor prognosis in patients with pancreatic cancer. These findings suggest that disrupted mitochondrial iron homeostasis may contribute to cancer development and hence constitute a target for therapeutic intervention.
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