Department of Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
Cancer Res. 2010 Dec 15;70(24):10213-23. doi: 10.1158/0008-5472.CAN-10-2720. Epub 2010 Oct 27.
The c-MYC protein participates in energy-consuming processes such as proliferation and ribosome biosynthesis, and its expression is often dysregulated in human cancers. Cancer cells distant from blood vessels in solid tumors are in short supply of oxygen and nutrition yet can adapt to the microenvironment and survive under metabolic stress. The role and regulation of c-MYC protein in the tumor microenvironment of limited energy sources are poorly understood. Here, we show that c-MYC protein levels in cancer cells are strikingly reduced in the area distant from the blood vessels in vivo and also under oxygen- and glucose-deprived conditions in vitro. The rapid reduction of c-MYC protein levels requires low levels of both oxygen and glucose, and under these conditions, downregulation is mainly achieved by enhanced degradation. Suppression of c-MYC protein levels by small hairpin RNA decreases the necrotic cell death induced by oxygen and glucose deprivation. Thus, the environmental milieu regulates c-MYC protein levels, and downregulation of c-MYC might be a strategy for cancer cells to survive under conditions of limited energy sources.
c-MYC 蛋白参与能量消耗过程，如增殖和核糖体生物合成，其表达在人类癌症中经常失调。实体肿瘤中远离血管的癌细胞缺氧和营养不足，但能够适应微环境并在代谢应激下存活。c-MYC 蛋白在有限能量来源的肿瘤微环境中的作用和调节知之甚少。在这里，我们表明，体内远离血管的区域以及体外缺氧和葡萄糖剥夺条件下，癌细胞中的 c-MYC 蛋白水平显著降低。c-MYC 蛋白水平的快速降低需要低氧和低糖水平，并且在这些条件下，下调主要通过增强降解来实现。通过短发夹 RNA 抑制 c-MYC 蛋白水平可减少缺氧和葡萄糖剥夺引起的坏死性细胞死亡。因此，环境调节 c-MYC 蛋白水平，下调 c-MYC 可能是癌细胞在有限能量来源条件下生存的一种策略。
