p53 and glucose metabolism: an orchestra to be directed in cancer therapy

Metabolic reprogramming is a hallmark of cancer with a strong impact on tumor cell survival, proliferation, dissemination, and resistance to therapy. As such, it has represented a promising therapeutic target for cancer. Although cancer cells may exhibit a wide range of metabolic profiles, the enhancement of aerobic glycolysis to generate lactate and ATP (Warburg effect) is a cancer-associated trait, which is under regulation of both oncogenes and tumor suppressor genes. Particularly, the tumor suppressor protein p53 was shown to revert the Warburg effect, and to negatively influence the oncogenic metabolic adaption of cancer cells. This review provides a systematization of the p53 influence on glycolysis and oxidative phosphorylation (OXPHOS), giving attention to the interplay of p53 with key signaling pathways, including c-Myc, HIF-1, LKB1/AMPK, and PI3K/Akt, as well as to mutant p53 gain-of-function. It also contributes to a better understanding of distinct metabolic profiles in heterogeneous tumor cell populations, and of its impact on cancer therapeutic resistance. Additionally, a reflection on current strategies adopted in clinical trials to overcome therapeutic resistance is presented, highlighting the main limitations and future therapeutic perspectives based on metabolic reprogramming. In particular, this review emphasizes the p53 activation as a promising therapeutic strategy to reprogram tumor glucose metabolism, conducting to cell death. Moreover, potential synergisms between p53-activating agents and metabolic inhibitors are discussed, fostering the improvement of cancer therapy.