p53 regulation of metabolic pathways

Abstract

During the course of tumorigenesis, cells acquire a number of alterations that contribute to the acquisition of the malignant phenotype, allowing them to survive and flourish in increasingly hostile environments. Cancer cells can be characterized by perturbations in the control of cell proliferation and growth, resistance to death, and alterations in their interactions with the microenvironment. Underpinning many of these changes are shifts in metabolism that allow cancer cells to use alternative pathways for energy production and building the macromolecules necessary for growth, as well as regulating the generation of signaling molecules such as reactive oxygen species (ROS). In the past few years, it became clear that p53, the most studied, if not most important, tumor suppressor protein, can also directly control metabolic traits of cells.

Figure 1.

The main energy-generating metabolic pathways, and their regulation by p53. By promoting oxidative phosphorylation and inhibiting glycolysis, p53 might oppose the Warburg effect that is seen in many cancers. Promotion of the pentose phosphate pathway would also provide survival functions and may contribute to anabolic pathways necessary for damage repair.

Figure 2.

p53 drives different responses under conditions of low stress (where cell survival and repair is supported) and high stress (where the damaged cell is eliminated though death or senescence). However, the inappropriate maintenance of the low-stress functions may contribute to cancer cell survival and growth.