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

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 (NMT). Myristoylation is emerging as a promising cancer therapeutic target; however, the molecular determinants of sensitivity...

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Published in:	Cancer research communications Vol. 4; no. 7; pp. 1815 - 1833
Main Authors:	Geroyska, Sofia, Mejia, Isabel, Chan, Alfred A, Navarrete, Marian, Pandey, Vijaya, Kharpatin, Samuel, Noguti, Juliana, Wang, Feng, Srole, Daniel, Chou, Tsui-Fen, Wohlschlegel, James, Nemeth, Elizabeta, Damoiseaux, Robert, Shackelford, David B, Lee, Delphine J, Díaz, Begoña
Format:	Journal Article
Language:	English
Published:	United States American Association for Cancer Research 01-07-2024
Subjects:	Acyltransferases - antagonists & inhibitors Acyltransferases - genetics AMP-Activated Protein Kinase Kinases Animals Cell Line, Tumor Humans Iron Overload - metabolism Kelch-Like ECH-Associated Protein 1 - genetics Kelch-Like ECH-Associated Protein 1 - metabolism Lung Neoplasms - drug therapy Lung Neoplasms - genetics Lung Neoplasms - metabolism Lung Neoplasms - pathology Membrane Transport Proteins - genetics Membrane Transport Proteins - metabolism Mice Mitochondria - drug effects Mitochondria - metabolism Mitochondrial Precursor Protein Import Complex Proteins Mutation Oxidative Stress - drug effects Protein Serine-Threonine Kinases - antagonists & inhibitors Protein Serine-Threonine Kinases - genetics Protein Serine-Threonine Kinases - metabolism Proto-Oncogene Proteins p21(ras) - genetics Proto-Oncogene Proteins p21(ras) - metabolism Xenograft Model Antitumor Assays
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Summary:	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 (NMT). Myristoylation is emerging as a promising cancer therapeutic target; however, the molecular determinants of sensitivity to NMT inhibition or the mechanism by which it induces cancer cell death are not completely understood. We report that NMTs 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 homolog 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 NMT-TIM17A as a potential therapeutic target in highly aggressive lung carcinomas. KRAS-mutant lung carcinomas with LKB1 and/or KEAP1 co-mutations have intrinsic therapeutic resistance. We show that these tumors are sensitive to NMT inhibitors, which slow tumor growth in vivo and sensitize cells to platinum-based chemotherapy in vitro. Inhibition of myristoylation causes death by parthanatos and thus has the potential to kill apoptosis and ferroptosis-resistant cancer cells. Our findings warrant investigation of NMT as a therapeutic target in highly aggressive lung carcinomas.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Current address for I. Mejia: Department of Molecular Biology, University of California, San Diego, La Jolla, California; and current address for M. Navarrete, Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California.
ISSN:	2767-9764 2767-9764
DOI:	10.1158/2767-9764.CRC-23-0428