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N-Myristoyltransferase Inhibition Induces ER-Stress, Cell Cycle Arrest, and Apoptosis in Cancer Cells

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Title: N-Myristoyltransferase Inhibition Induces ER-Stress, Cell Cycle Arrest, and Apoptosis in Cancer Cells
Authors: Thinon, E
Morales Sanfrutos, J
Mann, D
Tate, EW
Item Type: Journal Article
Abstract: 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 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.
Issue Date: 7-Jun-2016
Date of Acceptance: 24-May-2016
URI: http://hdl.handle.net/10044/1/33254
DOI: https://dx.doi.org/10.1021/acschembio.6b00371
ISSN: 1554-8937
Publisher: American Chemical Society
Start Page: 2165
End Page: 2176
Journal / Book Title: ACS Chemical Biology
Volume: 11
Issue: 8
Copyright Statement: This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Sponsor/Funder: Biotechnology and Biological Sciences Research Council (BBSRC)
Cancer Research UK
Cancer Research UK
Cancer Research UK
Funder's Grant Number: BB/D02014X/1
C29637/A9913
C29637/A10711
C29637/A20183
Keywords: Organic Chemistry
03 Chemical Sciences
06 Biological Sciences
Publication Status: Published
Appears in Collections:Chemistry
Biological and Biophysical Chemistry
Faculty of Natural Sciences



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