Autophagy fuels mitochondrial function through regulation of iron metabolism in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest 5-year survival rates of any cancer in the United States. Our previous work has shown that autophagy can promote PDAC progression. We recently established the importance of autophagy in regulating bioavailable iron to control mitochondria...

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Bibliographic Details
Published in:Autophagy 2024-04, Vol.20 (4), p.963-964
Main Authors: Mukhopadhyay, Subhadip, Encarnacion-Rosado, Joel, Kimmelman, Alec C.
Format: Article
Language:English
Subjects:
Animals
Autophagic Punctum
Autophagy
Autophagy - physiology
cancer associated fibroblasts
Cancer-Associated Fibroblasts - metabolism
Cancer-Associated Fibroblasts - pathology
Carcinoma, Pancreatic Ductal - metabolism
Carcinoma, Pancreatic Ductal - pathology
Cell Line, Tumor
Humans
Iron - metabolism
lysosome
Mice
mitochondria
Mitochondria - metabolism
pancreatic ductal adenocarcinoma
Pancreatic Neoplasms - metabolism
Pancreatic Neoplasms - pathology
Succinate Dehydrogenase - metabolism
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Summary:Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest 5-year survival rates of any cancer in the United States. Our previous work has shown that autophagy can promote PDAC progression. We recently established the importance of autophagy in regulating bioavailable iron to control mitochondrial metabolism in PDAC. We found that inhibition of autophagy in PDAC leads to mitochondrial dysfunction due to abrogation of succinate dehydrogenase complex iron sulfur subunit B (SDHB) expression. Additionally, we observed that cancer-associated fibroblasts (CAFs) can provide iron to autophagy-inhibited PDAC tumor cells, thereby increasing their resistance to autophagy inhibition. To impede such metabolic compensation, we used a low iron diet together with autophagy inhibition and demonstrated a significant improvement of tumor response in syngeneic PDAC models. Abbreviations: PDAC: Pancreatic ductal adenocarcinoma; CAFs: cancer-associated fibroblasts; SDHB: succinate dehydrogenase complex iron sulfur subunit B; ISCA1: iron sulfur cluster assembly protein 1; FPN: ferroportin; LIP: labile iron pool; FAC: ferric ammonium chloride; OCR: oxygen consumption rate; OXPHOS: oxidative phosphorylation, IL6: interleukin 6; Fe-S: iron sulfur; ATP: adenosine triphosphate.
ISSN:1554-8627
1554-8635
1554-8635
DOI:10.1080/15548627.2023.2223473