A new study led by the University of Michigan Rogel Cancer Center demonstrates how inhibiting a key enzyme known as GOT1 can flip a switch in the cancer cells -- causing them to shift from using nutrients to fuel growth toward conserving them to maintain energy levels.

In this state, the cancer cells release their iron stores and become vulnerable to a form of programmed, iron-dependent cell death known as ferroptosis, according to findings in cell cultures that appear in Nature Communications.

"If pancreatic cancer's success comes from approaching nutrient metabolism differently than other cancers, our goal is to target aspects of that metabolism for therapeutic benefit," said study senior author Costas Lyssiotis, Ph.D., an associate professor of molecular and integrative physiology and of internal medicine at U-M.

The study was led by first author Daniel Kremer, Ph.D., a recent graduate of U-M Program in Chemical Biology and former member of the Lyssiotis lab.

The GOT1 pathway helps the cancer cells maintain their energy balance, Kremer explained.

"When we inhibit the enzyme, it doesn't kill the cell, but it puts it into a state of energetic stress, so it has to use those nutrients to maintain the cell rather than for growth," he said. "This study describes the mechanisms of that process and how we might be able to exploit it to trigger cell death through ferroptosis."

Key collaborators on the project include Yatrik Shah, Ph.D., of the Rogel Cancer Center and Kenneth Olive, Ph.D., of Columbia University and the Herbert Irving Comprehensive Cancer Center.

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Materials provided by Michigan Medicine - University of Michigan. Original written by Ian Demsky. Note: Content may be edited for style and length.

Journal Reference:

1. 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 di Magliano, Howard C. Crawford, Yatrik M. Shah, Kenneth P. Olive, Costas A. Lyssiotis. GOT1 inhibition promotes pancreatic cancer cell death by ferroptosis. Nature Communications, 2021; 12 (1) DOI: 10.1038/s41467-021-24859-2