GOT1 inhibition promotes pancreatic cancer cell death by ferroptosis

• DOI: 10.1038/s41467-021-24859-2
• Publication Date: 2021-08-11T10:09:03Z
• Authors: Daniel M. Kremer; Barbara S. Nelson; Lin Lin; Emily L. Yarosz; Christopher J. Ha...; 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 di M...; Howard C. Crawford; Yatrik M. Shah; Kenneth P. Olive; Costas A. Lyssiotis
• Keywords: Catabolism

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