Role of p38α/MAPK14 in glucose metabolism and autophagy modulation during starvation

Increased anaerobic glycolysis is a common feature of many cancer cells, which have adapted their metabolism to maximize glucose incorporation and catabolism to generate ATP and substrates for biosynthetic reactions. This phenomenon is known as the “Warburg effect”. Indeed, glycolysis allows a more rapid production of ATP compared to oxidative phosphorylation, and provides metabolic intermediates required for the high proliferation of cancer cells. Moreover, it makes cancer cells less sensitive to fluctuations of oxygen levels, a condition usually occurring in a newly established tumor environment. Indeed, blood vessels do not penetrate deeply into the core of a solid tumor, limiting, other than oxygen, nutrients supply. Here, we provide evidence for a dual role of p38/MAPK14 in driving a rearrangement of glucose metabolism in condition of nutrient deprivation. We demonstrate that p38/MAPK14 is activated during nutrient deprivation in a ROS dependent way and affects glucose metabolism at two different levels: on the one hand, it increases Glut-3/SLC2A3 mRNA and protein levels, resulting in a higher incorporation of glucose within the cell. This event involves the p38/MAPK14-mediated enhancement of HIF1A protein stability. On the other hand, p38/MAPK14 mediates a metabolic shift from glycolysis to the pentose phosphate pathway (PPP) through the induction of PFKFB3 (6phosphofructo-2-kinase/fructose 2, 6-bisphosphatase 3) degradation by the proteasome. This event requires the presence of two distinct degradation sequences on PFKFB3, namely KEN box and DSG motif Ser273, which are recognized by two different E3 ligase complexes. The p38/MAPK14-driven metabolic reprogramming sustains the production of NADPH, an important cofactor for many anabolic reactions and for the maintenance of the proper intracellular redox environment. Indeed, ROS levels are controlled by a delicate balance between low acting as signaling molecules, and high resulting in cellular damage and death. We investigated the consequences of this metabolic rearrangement on autophagy induction and found that the final effect of p38/MAPK14 activation and reduced ROS production is a buffer of autophagic flux that confers cancer resistance to nutrient deprivation. Indeed, if kept at low levels, autophagy is an important prosurvival process but, if uncontrolled, it can lead to cell death. Taken together, our results establish a new role for p38/MAPK14 in promoting tumor cells survival under metabolic stress, making the kinase at the center stage of anti-cancer therapy raised against glycolysis-addicted tumor.