N-Myristoyltransferase Inhibition Induces ER-Stress, Cell Cycle Arrest, and Apoptosis in Cancer Cells.
N-Myristoyltransferase (NMT) covalently attaches a C14 fatty acid to the N-terminal glycine of proteins and has been proposed as a therapeutic target in cancer. We have recently shown that selective NMT inhibition leads to dose-responsive loss of N-myristoylation on more than 100 protein targets in cells, and cytotoxicity in cancer cells. N-myristoylation lies upstream of multiple pro-proliferative and oncogenic pathways, but to date the complex substrate specificity of NMT has limited determination of which diseases are most likely to respond to a selective NMT inhibitor. We describe here the phenotype of NMT inhibition in HeLa cells and show that cells die through apoptosis following or concurrent with accumulation in the G1 phase. We used quantitative proteomics to map protein expression changes for more than 2700 proteins in response to treatment with an NMT inhibitor in HeLa cells and observed down-regulation of proteins involved in cell cycle regulation and up-regulation of proteins involved in the endoplasmic reticulum stress and unfolded protein response, with similar results in breast (MCF-7, MDA-MB-231) and colon (HCT116) cancer cell lines. This study describes the cellular response to NMT inhibition at the proteome level and provides a starting point for selective targeting of specific diseases with NMT inhibitors, potentially in combination with other targeted agents.
Department of Chemistry, Imperial College London , Exhibition Road, London SW72AZ, United Kingdom.|Department of Life Sciences, Imperial College London , Exhibition Road, London SW72AZ, United Kingdom.
Emmanuelle
E
Thinon
Department of Chemistry, Imperial College London , Exhibition Road, London SW72AZ, United Kingdom.
Julia
J
Morales-Sanfrutos
Department of Life Sciences, Imperial College London , Exhibition Road, London SW72AZ, United Kingdom.|Institute of Chemical Biology, Department of Chemistry, Imperial College London , Exhibition Road, London SW72AZ, United Kingdom.
David J
DJ
Mann
Department of Chemistry, Imperial College London , Exhibition Road, London SW72AZ, United Kingdom.|Institute of Chemical Biology, Department of Chemistry, Imperial College London , Exhibition Road, London SW72AZ, United Kingdom.
Edward W
EW
Tate
D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D020543:Proteome
D004791:Enzyme Inhibitors; D020543:Proteome; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase