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Abstract
Myristoylation is one of key post-translational modifications that involved in signal transduction, cellular transformation and tumorigenesis. Increasing evidence demonstrates that targeting myristoylation might provide a new strategy for eliminating cancers. However, the underlying mechanisms are still yielded unclear. In this study, we demonstrated that genetic inhibition of N-myristoyltransferase NMT1 suppressed initiation, proliferation and invasion of breast cancer cells either in vitro or in vivo. We identified ROS could negatively regulate NMT1 expression and NMT1 knockdown conversely promoted oxidative stress, which formed a feedback loop. Furthermore, inhibition of NMT1 caused degraded proteins increase and ER stress, which cross-talked with mitochondria to produce more ROS. And both of oxidative stress and ER stress could activate JNK pathway, leading to autophagy which abrogated breast cancer progression especially triple-negative breast cancer (TNBC). These studies provide a preclinical proof of concept for targeting NMT1 as a strategy to treat breast cancer.
Highlights
Breast cancer is one of the leading causes for mortality of women around the world
In this study, we demonstrate that NMT1 is capable of modulating breast cancer cell initiation and promoting cell proliferation and invasion through intracellular stress induced Jun N-terminal kinase (JNK) pathway activation both in vitro and in vivo
(see figure on previous page) Fig. 4 JNK pathway plays a key role in breast cancer progression mediated by NMT1 knockdown. a The Human Phospho-Kinase Array was used to detect multiple phosphorylated kinases in Shctrl and ShNMT1-infected SUM149 cells
Summary
Genomic studies have identified five major breast cancer intrinsic subtypes: luminal A, Luminal B, HER2-enriched, basal-like, and claudin-low, that show significant differences in incidence, survival, and response to therapies[1,2]. Basal-like and claudin-low breast cancers still lack effective ways of treatment due to absence of approved hormone, targeted therapeutic options and frequently poor response to standard chemotherapies[3]. Previous reports demonstrated that basal-like, especially claudin-low subtype, is enriched for breast tumor initiating cells (BTIC) features[4,5,6]. Our previous studies have shown that BTIC with the enzyme aldehyde dehydrogenase (ALDH) activity (ALDH-positive) are enriched for tumor-initiating characteristics[7]. Therapeutic target on ALDH positive population might provide insights to treat triple-negative breast cancers
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