Parthanatos: Mechanisms, modulation, and therapeutic prospects in neurodegenerative disease and stroke

Yang, Liu; Guttman, Lauren; Dawson, Valina L.; Dawson, Ted M.

doi:10.1016/j.bcp.2024.116174

Cited by 5 publications

(1 citation statement)

References 214 publications

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“…Parthanatos, however, is independent of caspase activation and dependent on PARP activation; thus, it can be rescued with PARP inhibitors. Parthanatos has been mostly studied in the context of neurodegenerative diseases and stroke, in which it was first described ( 42 , 46 ). However, recent findings indicate that cancer cells are also susceptible to parthanatos ( 47 , 48 ), which represents a therapeutic opportunity to kill cancer cells that are resistant to other types of death.…”

Section: Introductionmentioning

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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