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Ferroptotic damage promotes pancreatic tumorigenesis through a TMEM173/STING-dependent DNA sensor pathway.

ABSTRACT: Ferroptosis is a more recently recognized form of cell death that relies on iron-mediated oxidative damage. Here, we evaluate the impact of high-iron diets or depletion of Gpx4, an antioxidant enzyme reported as an important ferroptosis suppressor, in the pancreas of mice with cerulean- or L-arginine-induced pancreatitis, and in an oncogenic Kras murine model of spontaneous pancreatic ductal adenocarcinoma (PDAC). We find that either high-iron diets or Gpx4 depletion promotes 8-OHG release and thus activates the TMEM173/STING-dependent DNA sensor pathway, which results in macrophage infiltration and activation during Kras-driven PDAC in mice. Consequently, the administration of liproxstatin-1 (a ferroptosis inhibitor), clophosome-mediated macrophage depletion, or pharmacological and genetic inhibition of the 8-OHG-TMEM173 pathway suppresses Kras-driven pancreatic tumorigenesis in mice. GPX4 is also a prognostic marker in patients with PDAC. These findings provide pathological and mechanistic insights into ferroptotic damage in PDAC tumorigenesis in mice.

SUBMITTER: Dai E

PROVIDER: S-EPMC7732843 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Ferroptotic damage promotes pancreatic tumorigenesis through a TMEM173/STING-dependent DNA sensor pathway.

Dai Enyong E Han Leng L Liu Jiao J Xie Yangchun Y Zeh Herbert J HJ Kang Rui R Bai Lulu L Tang Daolin D

Nature communications 20201211 1

Ferroptosis is a more recently recognized form of cell death that relies on iron-mediated oxidative damage. Here, we evaluate the impact of high-iron diets or depletion of Gpx4, an antioxidant enzyme reported as an important ferroptosis suppressor, in the pancreas of mice with cerulean- or L-arginine-induced pancreatitis, and in an oncogenic Kras murine model of spontaneous pancreatic ductal adenocarcinoma (PDAC). We find that either high-iron diets or Gpx4 depletion promotes 8-OHG release and t ...[more]

PMID: 33311482

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Project description:Diabetic cardiomyopathy (DCM) is a serious cardiac complication of diabetes that currently lacks specific treatment. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has been suggested to contribute to the pathogenesis of cardiovascular diseases. However, whether cGAS-STING is involved in the development of DCM has not been established. Our study aimed to determine the role of cGAS-STING in the initiation of nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome-induced cardiac pyroptosis and chronic inflammation during the pathogenesis of DCM. C57BL/6J mice were preinjected with adeno-associated virus 9 (AAV9) intravenously via the tail vein to specifically knock down myocardial STING. After four weeks, mice with myocardium-specific knockdown of STING received injections of streptozotocin (STZ; 50 mg/kg) and a high-fat diet to induce diabetes. Measurements included echocardiography, immunohistochemical analyses, wheat germ agglutinin (WGA) staining, and western blotting. Here, we showed that the cGAS-STING signaling pathway was activated in diabetic hearts, which was indicated by the increased phosphorylation of TANK-binding kinase 1 (TBK1) and interferon (IFN) regulatory factor 3 (IRF3), leading to the activation of the NLRP3 inflammasome in the hearts of diabetic mice and proinflammatory cytokine release into serum. Moreover, STING knockdown via adeno-associated virus-9 (AAV9) in diabetic mouse heart alleviated cardiac pyroptosis and the inflammatory response, prevented diabetes-induced hypertrophy, and restored cardiac function. Mechanistically, we showed that palmitic acid (PA)-induced lipotoxicity impairs mitochondrial homeostasis, producing excessive mitochondrial reactive oxygen species (mtROS), which results in oxidative damage to mitochondrial DNA (mtDNA) and its release into the cytoplasm while switching on cGAS-STING-mediated pyroptosis in cardiomyocytes, thereby worsening the progression of diabetic cardiomyopathy. Our study demonstrated that activation of the cGAS-STING pathway caused by mitochondrial oxidative damage and mtDNA escape induced by free fatty acids promoted pyroptosis and proinflammatory responses in cardiomyocytes in a NLRP3 inflammasome-dependent manner, thus promoting myocardial hypertrophy during the progression of DCM.

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Ferroptotic damage promotes pancreatic tumorigenesis through a TMEM173/STING-dependent DNA sensor pathway.

Publications

Ferroptotic damage promotes pancreatic tumorigenesis through a TMEM173/STING-dependent DNA sensor pathway.

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