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15357163mct181323-sup-213000_2_supp_5490442_pqs6mm.mp4 (22.68 MB)

Supplementary Video S1B from Targeting Mitochondrial Proline Dehydrogenase with a Suicide Inhibitor to Exploit Synthetic Lethal Interactions with p53 Upregulation and Glutaminase Inhibition

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posted on 2023-04-03, 15:21 authored by 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

To demonstrate that the oral N-PPG treatment (treated flies in Suppl. Fig 3B panel A) phenocopies the Sluggish-A phenotype of SlgA null mutant flies as previously described (18), geotaxis of untreated SlgA mutant flies is video illustrated (right tube) and compared to that of untreated wildtype flies (left tube).

Funding

Elizabeth MA Stevens memorial funding

Alfred Benzon Fellowship

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ARTICLE ABSTRACT

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 (S-5-oxo: S-5-oxo-2-tetrahydrofurancarboxylic acid) or irreversible (N-PPG: N-propargylglycine) PRODH inhibitor. Unlike 5-oxo, the suicide inhibitor N-PPG induces early and selective decay of PRODH protein without triggering mitochondrial destruction, consistent with N-PPG activation of the mitochondrial unfolded protein response. Fly and breast tumor (MCF7)-xenografted mouse studies indicate that N-PPG doses sufficient to phenocopy PRODH knockout and induce its decay can be safely and effectively administered in vivo. 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 (S-5-oxo and N-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 in vitro when the PRODH suicide inhibitor, N-PPG, is combined with both GLS1-inhibiting and a p53-upregulating MDM2 antagonist. These findings provide preclinical rationale for the development of N-PPG–like PRODH inhibitors as cancer therapeutics to exploit synthetic lethal interactions with p53 upregulation and GLS1 inhibition.

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    Molecular Cancer Therapeutics

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