The metabolism of colorectal cancer adapting to nutritional stress

Tumor cells respond to their microenvironment, which includes hypoxia and malnutrition, and adapt their metabolism to survive and grow. Some oncogenes are associated with cancer metabolism via regulation of the related enzymes or transporters. However, the importance of metabolism and precise metabolic effects of oncogenes in colorectal cancer remain unclear. We found that colorectal cancer cells could survive under the condition of glucose depletion and that their resistance to such conditions was dependent on not KRAS mutation alone but whole genomic alterations. Metabolome analysis of those cells demonstrated the maintenance of tricarboxylic acid (TCA) cycle activity and anabolic processes under such conditions. Furthermore, we revealed a pivotal role of GLUD1, a key enzyme related to glutaminolysis, and SLC25A13 coding the aspartate–glutamate carrier (AGC) that composed malate–aspartate shuttle in cells. Colorectal cancer cells that are resistant to glucose depletion positively regulate GLUD1 to replenish TCA cycle metabolites and produce energy. Furthermore, they negatively regulate SLC25A13 to decrease reactive oxygen species (ROS) production. High expression of Glud 1 or low expression of Slc25a13 was associated with tumor aggressiveness and worse prognosis by immunohistochemistry of colorectal cancer specimens. Furthermore, high expression of Glud1 combined with low expression of Slc25a13 had a higher association with tumor aggression and poor prognosis than did individual expression of each. In conclusion, Glud1 and Slc25a13 may serve as new targets in treating refractory colorectal cancer. Understanding the inherent metabolism of each cancer type can result in development of cancer therapy. Colorectal cancer cell line DLD1 and HT29 under glucose- and glutamine-containing conditions and glucose-deprived conditions