Pharmacologic inhibition of MIF nuclease: A new treatment paradigm to treat cell death

Biswas, Devanik; Dawson, Valina L.; Dawson, Ted M.

doi:10.1002/ctm2.1044

Cited by 7 publications

(3 citation statements)

References 17 publications

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“…Parthanatos is a type of apoptosis-independent programmed cell death characterized by extensive oxidative stress ( 42 ). During parthanatos, PARP is hyperactivated and causes extensive poly-ADP-ribosylation (PARylation) of proteins, including AIF, which then translocates from mitochondria to the nuclei along with MIF ( 58 ), causing fragmentation of DNA into large fragments, and cell death (see diagram in Fig. 4B ).…”

Section: Resultsmentioning

confidence: 99%

N-Myristoytransferase Inhibition Causes Mitochondrial Iron Overload and Parthanatos in TIM17A-Dependent Aggressive Lung Carcinoma

Geroyska,

Mejia,

Chan

et al. 2024

Cancer Research Communications

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Myristoylation is a type of protein acylation by which the fatty acid myristate is added to the N-terminus of target proteins, a process mediated by N-myristoyltransferases. Myristoylation is emerging as a promising cancer therapeutic target, however the molecular determinants of sensitivity to N-myristoyltransferase inhibition or the mechanism by which it induces cancer cell death are not completely understood. We report that N-myristoyltransferases are a novel therapeutic target in lung carcinoma cells with LKB1 and/or KEAP1 mutations in a KRAS mutant background. Inhibition of myristoylation decreases cell viability in vitro and tumor growth in vivo. Inhibition of myristoylation causes mitochondrial ferrous iron overload, oxidative stress, elevated protein poly (ADP)-ribosylation and death by parthanatos. Furthermore, NMT inhibitors sensitized lung carcinoma cells to platinum-based chemotherapy. Unexpectedly, the mitochondrial transporter Translocase of Inner Mitochondrial Membrane 17 homologue A (TIM17A) is a critical target of myristoylation inhibitors in these cells. TIM17A silencing recapitulated the effects of NMT inhibition at inducing mitochondrial ferrous iron overload and parthanatos. Furthermore, sensitivity of lung carcinoma cells to myristoylation inhibition correlated with their dependency on TIM17A. This study reveals the unexpected connection between protein myristoylation, the mitochondrial import machinery, and iron homeostasis. It also uncovers myristoylation inhibitors as novel inducers of parthanatos in cancer, and the novel axis N-myristoyltransferase-TIM17A as a potential therapeutic target in highly aggressive lung carcinomas.

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Section: Resultsmentioning

confidence: 99%

N-Myristoytransferase Inhibition Causes Mitochondrial Iron Overload and Parthanatos in TIM17A-Dependent Aggressive Lung Carcinoma

Geroyska,

Mejia,

Chan

et al. 2024

Cancer Research Communications

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“…In 2016, macrophage migration inhibitory factor (MIF) was identified as a crucial factor in the induction of parthanatos by forming a MIF/AIF complex that translocates from the cytosol to the nucleus triggering DNA fragmentation and cell death. Considering that AIF does not possess any nuclease activity, MIF was assigned as a parthanatos-associated AIF nuclease (PAAN). , The research concept to interfere with this interaction to prevent parthanatos using the peptide-like inhibitor PAANIB-1 was suggested by Dawson in 2022 . Overall, discovering a role for the MIF/AIF interaction in PARP-1-mediated cell death indicates a potential for small-molecule modulation of this interaction.…”

Section: Introductionmentioning

confidence: 99%

“…Considering that AIF does not possess any nuclease activity, MIF was assigned as a parthanatos-associated AIF nuclease (PAAN). 10 , 11 The research concept to interfere with this interaction to prevent parthanatos using the peptide-like inhibitor PAANIB-1 was suggested by Dawson in 2022. 12 Overall, discovering a role for the MIF/AIF interaction in PARP-1-mediated cell death indicates a potential for small-molecule modulation of this interaction.…”

Section: Introductionmentioning

confidence: 99%

Allosteric Inhibitors of Macrophage Migration Inhibitory Factor (MIF) Interfere with Apoptosis-Inducing Factor (AIF) Co-Localization to Prevent Parthanatos

Chen,

Osipyan,

Adriana

et al. 2023

J. Med. Chem.

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Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine and essential signaling protein associated with inflammation and cancers. One of the newly described roles of MIF is binding to apoptosis-inducing factor (AIF) that “brings” cells to death in pathological conditions. The interaction between MIF and AIF and their nuclear translocation stands as a central event in parthanatos. However, classical competitive MIF tautomerase inhibitors do not interfere with MIF functions in parthanatos. In this study, we employed a pharmacophore-switch to provide allosteric MIF tautomerase inhibitors that interfere with the MIF/AIF co-localization. Synthesis and screening of a focused compound collection around the 1,2,3-triazole core enabled identification of the allosteric tautomerase MIF inhibitor 6y with low micromolar potency (IC50 = 1.7 ± 0.1 μM). This inhibitor prevented MIF/AIF nuclear translocation and protects cells from parthanatos. These findings indicate that alternative modes to target MIF hold promise to investigate MIF function in parthanatos-mediated diseases.

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