Abstract
N-myristoyltransferase-1 (NMT1) catalyzes protein myristoylation, a lipid modification that is elevated in cancer cells. NMT1 sustains proliferation and/or survival of cancer cells through mechanisms that are not completely understood. We used genetic and pharmacological inhibition of NMT1 to further dissect the role of this enzyme in cancer, and found an unexpected essential role for NMT1 at promoting lysosomal metabolic functions. Lysosomes mediate enzymatic degradation of vesicle cargo, and also serve as functional platforms for mTORC1 activation. We show that NMT1 is required for both lysosomal functions in cancer cells. Inhibition of NMT1 impaired lysosomal degradation leading to autophagy flux blockade, and simultaneously caused the dissociation of mTOR from the surface of lysosomes leading to decreased mTORC1 activation. The regulation of lysosomal metabolic functions by NMT1 was largely mediated through the lysosomal adaptor LAMTOR1. Accordingly, genetic targeting of LAMTOR1 recapitulated most of the lysosomal defects of targeting NMT1, including defective lysosomal degradation. Pharmacological inhibition of NMT1 reduced tumor growth, and tumors from treated animals had increased apoptosis and displayed markers of lysosomal dysfunction. Our findings suggest that compounds targeting NMT1 may have therapeutic benefit in cancer by preventing mTORC1 activation and simultaneously blocking lysosomal degradation, leading to cancer cell death.
Highlights
N-myristoyltransferase-1 (NMT1) catalyzes protein myristoylation, a lipid modification that is elevated in cancer cells
Western blotting (WB) revealed that NMT1 protein expression was reduced between 50 and 60% (Fig. 1A), and no compensatory induction of NMT2 expression was observed in KD clones (Supplementary Fig. S1)
In this study we report that NMT1 is an essential regulator of lysosomal metabolic functions in cancer cells
Summary
N-myristoyltransferase-1 (NMT1) catalyzes protein myristoylation, a lipid modification that is elevated in cancer cells. Our findings suggest that compounds targeting NMT1 may have therapeutic benefit in cancer by preventing mTORC1 activation and simultaneously blocking lysosomal degradation, leading to cancer cell death. Densitometry values (arbitrary units) for NMT1 signal normalized to actin in one representative experiment from two independent experiments. Representative pictures of LC3B and DAPI staining of H460 cells treated with DMSO or NMTi for 48 h. WB results for LC3BII, p 62SQSTM and actin (loading control) are shown for one representative experiment from two independent experiments with similar results. Nutrient depletion and mTORC1 inactivation leads to de-phosphorylation, nuclear translocation, and transcriptional activation of a network of genes involved in lysosomal biogenesis and a utophagy[33,34,35,36]
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