Department of Pharmacology, SUNY Upstate Medical University, Syracuse, New York, USA.
Gulfstream Diagnostics-Genomics, Dallas, Texas, USA.
Oncogene. 2018 Apr;37(15):2052-2066. doi: 10.1038/s41388-017-0051-9. Epub 2018 Jan 26.
A better understanding of the link between cellular metabolism and tumorigenesis is needed. Here, we report characterization of a novel protein named coiled-coil helix tumor and metabolism 1 (CHTM1). We have found that CHTM1 is associated with cancer and cellular metabolism. CHTM1 localizes to mitochondria and cytosol, and its deficiency in cancer cells results in decreased mitochondrial oxygen consumption and ATP levels as well as oxidative stress indicating mitochondrial dysfunction. CHTM1-deficient cancer cells display poor growth under glucose/glutamine-deprived conditions, whereas cells expressing increased levels of exogenous CHTM1 exhibit enhanced proliferation and survival under similar conditions. CHTM1 deficiency also leads to defects in lipid metabolism resulting in fatty acid accumulation, which explains poor growth of CHTM1-deficient cells under glucose/glutamine deprivation since nutrient deprivation increases dependency on lipids for energy generation. We also demonstrate that CHTM1 mediates its effect via the PKC, CREB, and PGC-1alpha signaling axis, and cytosolic accumulation of CHTM1 during nutrient deprivation appears to be important for its effect on cellular signaling events. Furthermore, analyses of tissue specimens from 71 breast and 97 colon cancer patients show CHTM1 expression to be upregulated in the majority of tumor specimens representing these malignancies. Collectively, our findings are highly significant because CHTM1 is a novel metabolic marker that is important for the growth of tumorigenic cells under limiting nutrient supplies and thus, links cellular metabolism and tumorigenesis.
需要更好地理解细胞代谢与肿瘤发生之间的联系。在这里，我们报告了一种名为卷曲螺旋结构域肿瘤和代谢 1（CHTM1）的新型蛋白的特征。我们发现 CHTM1 与癌症和细胞代谢有关。CHTM1 定位于线粒体和细胞质，其在癌细胞中的缺乏导致线粒体耗氧量和 ATP 水平降低以及氧化应激，表明线粒体功能障碍。在葡萄糖/谷氨酰胺剥夺条件下，缺乏 CHTM1 的癌细胞生长不良，而表达高水平外源性 CHTM1 的细胞在类似条件下表现出增强的增殖和存活。CHTM1 缺乏也导致脂质代谢缺陷，导致脂肪酸积累，这解释了缺乏 CHTM1 的细胞在葡萄糖/谷氨酰胺剥夺下生长不良的原因，因为营养剥夺增加了对脂质产生能量的依赖。我们还证明 CHTM1 通过 PKC、CREB 和 PGC-1alpha 信号轴发挥其作用，并且在营养剥夺期间 CHTM1 的细胞质积累对于其对细胞信号事件的影响似乎很重要。此外，对来自 71 例乳腺癌和 97 例结肠癌患者的组织标本的分析表明，CHTM1 在代表这些恶性肿瘤的大多数肿瘤标本中表达上调。总的来说，我们的发现非常重要，因为 CHTM1 是一种新型代谢标志物，对于在有限的营养供应下肿瘤细胞的生长很重要，因此，它将细胞代谢与肿瘤发生联系起来。
