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

ABSTRACT

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.

KEYWORDS:

• Autophagy
• lysosome
• mitochondria
• iron metabolism
• pancreatic ductal adenocarcinoma
• cancer associated fibroblasts

Disclosure statement

A.C.K. has financial interests in Vescor Therapeutics and is an inventor on patents pertaining to KRAS- regulated metabolic pathways and redox control pathways in pancreatic cancer, targeting GOT1 as a therapeutic approach, targeting alanine transport, and the autophagic control of iron metabolism. A.C.K. is on the scientific advisory board of Rafael/Cornerstone Pharmaceuticals, is an advisor to OncoRev, and has been a consultant for Deciphera and Abbvie. The other authors declare that they have no competing interests.

Supplemental data

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15548627.2023.2223473

Additional information

Funding

A.C.K is supported by NCI (grants P01CA117969, R35CA232124, P30CA016087-38, and 1R01CA251726-01A1), the Lustgarten Foundation, and SU2C; HHMI Gilliam Fellowships for Advanced Study to J.E.R.