Downregulation of c-MYC protein levels contributes to cancer cell survival under dual deficiency of oxygen and glucose.

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.