Targeting Mitochondrial Proline Dehydrogenase with a Suicide Inhibitor to Exploit Synthetic Lethal Interactions with p53 Upregulation and Glutaminase Inhibition.
Gary K Scott, Christina Yau, Beatrice C Becker, Sana Khateeb, Sophia Mahoney, Martin Borch Jensen, Byron Hann, Bryan J Cowen, Scott D Pegan, Christopher C Benz
Author Information
Gary K Scott: Buck Institute for Research on Aging, Novato, California.
Christina Yau: Buck Institute for Research on Aging, Novato, California.
Beatrice C Becker: Buck Institute for Research on Aging, Novato, California.
Sana Khateeb: Buck Institute for Research on Aging, Novato, California.
Sophia Mahoney: Buck Institute for Research on Aging, Novato, California.
Martin Borch Jensen: Buck Institute for Research on Aging, Novato, California.
Byron Hann: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California. ORCID
Bryan J Cowen: Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado.
Scott D Pegan: Center for Drug Discovery, College of Pharmacy, University of Georgia, Athens, Georgia.
Christopher C Benz: Buck Institute for Research on Aging, Novato, California. cbenz@buckinstitute.org.
Proline dehydrogenase (PRODH) is a p53-inducible inner mitochondrial membrane flavoprotein linked to electron transport for anaplerotic glutamate and ATP production, most critical for cancer cell survival under microenvironmental stress conditions. Proposing that PRODH is a unique mitochondrial cancer target, we structurally model and compare its cancer cell activity and consequences upon exposure to either a reversible (-5-oxo: -5-oxo-2-tetrahydrofurancarboxylic acid) or irreversible (-PPG: -propargylglycine) PRODH inhibitor. Unlike 5-oxo, the suicide inhibitor -PPG induces early and selective decay of PRODH protein without triggering mitochondrial destruction, consistent with -PPG activation of the mitochondrial unfolded protein response. Fly and breast tumor (MCF7)-xenografted mouse studies indicate that -PPG doses sufficient to phenocopy PRODH knockout and induce its decay can be safely and effectively administered Among breast cancer cell lines and tumor samples, PRODH mRNA expression is subtype dependent and inversely correlated with glutaminase (GLS1) expression; combining inhibitors of PRODH (-5-oxo and -PPG) and GLS1 (CB-839) produces additive if not synergistic loss of cancer cell (ZR-75-1, MCF7, DU4475, and BT474) growth and viability. Although PRODH knockdown alone can induce cancer cell apoptosis, the anticancer potential of either reversible or irreversible PRODH inhibitors is strongly enhanced when p53 is simultaneously upregulated by an MDM2 antagonist (MI-63 and nutlin-3). However, maximum anticancer synergy is observed when the PRODH suicide inhibitor, -PPG, is combined with both GLS1-inhibiting and a p53-upregulating MDM2 antagonist. These findings provide preclinical rationale for the development of -PPG-like PRODH inhibitors as cancer therapeutics to exploit synthetic lethal interactions with p53 upregulation and GLS1 inhibition.
