GOT1 inhibition promotes pancreatic cancer cell death by ferroptosis

Daniel M. Kremer, Barbara S. Nelson, Lin Lin, Emily L. Yarosz, Christopher J. Halbrook, Samuel A. Kerk, Peter Sajjakulnukit, Amy Myers, Galloway Thurston, Sean W. Hou, Eileen S. Carpenter, Anthony C. Andren, Zeribe C. Nwosu, Nicholas Cusmano, Stephanie Wisner, Nneka E. Mbah, Mengrou Shan, Nupur K. Das, Brian Magnuson, Andrew C. LittleMilan R. Savani, Johanna Ramos, Tina Gao, Stephen A. Sastra, Carmine F. Palermo, Michael A. Badgley, Li Zhang, John M. Asara, Samuel K. McBrayer, Marina Pasca di Magliano, Howard C. Crawford, Yatrik M. Shah, Kenneth P. Olive, Costas A. Lyssiotis

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Cancer metabolism is rewired to support cell survival in response to intrinsic and environmental stressors. Identification of strategies to target these adaptions is an area of active research. We previously described a cytosolic aspartate aminotransaminase (GOT1)-driven pathway in pancreatic cancer used to maintain redox balance. Here, we sought to identify metabolic dependencies following GOT1 inhibition to exploit this feature of pancreatic cancer and to provide additional insight into regulation of redox metabolism. Using pharmacological methods, we identify cysteine, glutathione, and lipid antioxidant function as metabolic vulnerabilities following GOT1 withdrawal. We demonstrate that targeting any of these pathways triggers ferroptosis, an oxidative, iron-dependent form of cell death, in GOT1 knockdown cells. Mechanistically, we reveal that GOT1 inhibition represses mitochondrial metabolism and promotes a catabolic state. Consequently, we find that this enhances labile iron availability through autophagy, which potentiates the activity of ferroptotic stimuli. Overall, our study identifies a biochemical connection between GOT1, iron regulation, and ferroptosis.

Original languageEnglish (US)
Article number4860
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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