Division of Medical Hematology Oncology, Department of Medicine, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
Division of Dermatology, Department of Medicine, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
Sci Rep. 2020 Jul 20;10(1):11952. doi: 10.1038/s41598-020-68615-w.
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.
N-豆蔻酰转移酶 1（NMT1）催化蛋白质豆蔻酰化，这是一种在癌细胞中升高的脂质修饰。NMT1 通过尚未完全阐明的机制维持癌细胞的增殖和/或存活。我们使用 NMT1 的遗传和药理学抑制来进一步剖析该酶在癌症中的作用，发现 NMT1 出人意料地在促进溶酶体代谢功能方面发挥着重要作用。溶酶体介导囊泡货物的酶促降解，也作为 mTORC1 激活的功能平台。我们表明 NMT1 是癌细胞中溶酶体功能所必需的。NMT1 的抑制会损害溶酶体降解，导致自噬通量受阻，同时导致 mTOR 从溶酶体表面解离，从而减少 mTORC1 的激活。NMT1 通过溶酶体衔接蛋白 LAMTOR1 对溶酶体代谢功能的调节在很大程度上是通过溶酶体衔接蛋白 LAMTOR1 介导的。因此，靶向 LAMTOR1 的基因靶向复制了靶向 NMT1 的大多数溶酶体缺陷，包括溶酶体降解缺陷。NMT1 的药理学抑制可减少肿瘤生长，并且来自治疗动物的肿瘤显示出增加的细胞凋亡和溶酶体功能障碍的标志物。我们的研究结果表明，靶向 NMT1 的化合物可能通过防止 mTORC1 激活并同时阻断溶酶体降解从而导致癌细胞死亡，从而在癌症治疗中具有治疗益处。
