Autophagy is critical for cysteine metabolism in pancreatic cancer through regulation of SLC7A11

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer. The elevated macroautophagy/autophagy in these tumors supports growth, promotes immune evasion, and increases therapeutic resistance. Therefore, targeting autophagy is a therapeutic strategy that is being pursued to tre...

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Bibliographic Details
Published in:Autophagy 2021-06, Vol.17 (6), p.1561-1562
Main Authors: Mukhopadhyay, Subhadip, Kimmelman, Alec C.
Format: Article
Language:English
Subjects:
Amino Acid Transport System y
Autophagic Punctum
Autophagy
Carcinoma, Pancreatic Ductal
Cell Line, Tumor
Cysteine
Humans
lysosome
metabolism
pancreatic ductal adenocarcinoma
Pancreatic Neoplasms
SLC7A11
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Summary:Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer. The elevated macroautophagy/autophagy in these tumors supports growth, promotes immune evasion, and increases therapeutic resistance. Therefore, targeting autophagy is a therapeutic strategy that is being pursued to treat PDAC patients. Whereas autophagy inhibition impairs mitochondrial metabolism in PDAC, the specific metabolite(s) that becomes limiting when autophagy is inhibited has not been identified. We report that loss of autophagy specifically results in intracellular cysteine depletion under nutrient-replete conditions. Mechanistically, we show that PDAC cells utilize the autophagy machinery to regulate the activity and localization of the cystine transporter SLC7A11 at the plasma membrane. Upon inhibition of autophagy, SLC7A11 is localized to lysosomes in an MTORC2-dependent manner. Our findings reveal a novel connection between autophagy and cysteine metabolism in pancreatic cancer.
ISSN:1554-8627
1554-8635
DOI:10.1080/15548627.2021.1922984