Journal Article

GOT1 inhibition promotes pancreatic cancer cell death by ferroptosis

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

2021

Overview

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. The aspartate aminotransaminase GOT1 is important for maintaining redox balance. Here, the authors show that inhibition of GOT1 in pancreatic cancer cells leads to cell death via ferroptosis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/106 / 14 / 14/34 / 38 / 38/91 / 631/67/1504/1713 / 631/67/2327 / 82/58 / 96 / 96/98 / Animals / Antioxidants / Antioxidants - pharmacology / Apoptosis / Aspartate Aminotransferase, Cytoplasmic - antagonists & inhibitors / Aspartate Aminotransferase, Cytoplasmic - genetics / Aspartate Aminotransferase, Cytoplasmic - metabolism / Autophagy / Cancer / Cell death / Cell Line, Tumor / Cell Proliferation / Cell survival / Cell Survival - drug effects / Cystine - metabolism / Environmental stress / Ferroptosis / Ferroptosis - drug effects / Glutathione / Glutathione - biosynthesis / Humanities and Social Sciences / Humans / Iron / Iron - metabolism / Lipids / Metabolism / Mice / Mitochondria / Mitochondria - metabolism / Mortality / multidisciplinary / Pancreatic cancer / Pancreatic Neoplasms - metabolism / Pancreatic Neoplasms - pathology / Phagocytosis / Science / Science (multidisciplinary) / Target recognition