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. Little, Milan 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 Magliano, Howard C. Crawford, Yatrik M. Shah, Kenneth P. Olive and Costas A. Lyssiotis ()
Additional contact information
Daniel M. Kremer: University of Michigan
Barbara S. Nelson: University of Michigan
Lin Lin: University of Michigan
Emily L. Yarosz: University of Michigan
Christopher J. Halbrook: University of Michigan
Samuel A. Kerk: University of Michigan
Peter Sajjakulnukit: University of Michigan
Amy Myers: University of Michigan
Galloway Thurston: University of Michigan
Sean W. Hou: University of Michigan
Eileen S. Carpenter: University of Michigan
Anthony C. Andren: University of Michigan
Zeribe C. Nwosu: University of Michigan
Nicholas Cusmano: University of Michigan
Stephanie Wisner: University of Michigan
Nneka E. Mbah: University of Michigan
Mengrou Shan: University of Michigan
Nupur K. Das: University of Michigan
Brian Magnuson: University of Michigan
Andrew C. Little: University of Michigan
Milan R. Savani: University of Texas Southwestern Medical Center
Johanna Ramos: University of Michigan
Tina Gao: University of Michigan
Stephen A. Sastra: Columbia University Medical Center
Carmine F. Palermo: Columbia University Medical Center
Michael A. Badgley: Columbia University Medical Center
Li Zhang: University of Michigan
John M. Asara: Beth Israel Deaconess Medical Center
Samuel K. McBrayer: University of Texas Southwestern Medical Center
Marina Pasca Magliano: University of Michigan
Howard C. Crawford: University of Michigan
Yatrik M. Shah: University of Michigan
Kenneth P. Olive: Columbia University Medical Center
Costas A. Lyssiotis: University of Michigan

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24859-2

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