Abstract
Metabolism plays critical roles in maintaining the homeostasis of cells. Metabolic abnormalities are often considered as one of the main driving forces for cancer progression, providing energy and substrates of biosynthesis to support neoplastic proliferation effectively. The tumor suppressor p53 is well known for its roles in inducing cell cycle arrest, apoptosis, senescence and ferroptosis. Recently, emerging evidence has shown that p53 is also actively involved in the reprogramming of cellular metabolism. In this review, we focus on recent advances in our understanding of the interplay between p53 and metabolism of glucose, fatty acid as well as amino acid, and discuss how the deregulation of p53 in these processes could lead to cancer.
Highlights
Reprogramming of cellular metabolism is one of the “hallmarks of cancer”, and is considered one of the main driving forces for tumorigenesis (Hanahan and Weinberg, 2011)
P53 represses the transcription of glucose transporters GLUT1, GLUT3, and GLUT4 to reduce glucose uptake, which is the first rate-limiting event in glycolysis (Kawauchi et al, 2008; Schwartzenberg-Bar-Yoseph et al, 2004). p53 transcriptionally induces TP53 Induced Glycolysis Regulatory Phosphatase (TIGAR) and inhibits 6-phosphofructo-2-kinase/ fructose-2,6-bisphosphatase (PFKFB3 and PFKFB4), resulting in reduced intracellular levels of fructose-2,6-bisphosphate (F-2,6BP), which functions as allosteric activator of phosphofructokinase (PFK), the rate-limiting enzyme catalyzing the conversion from F6P to F-1,6-BP (Bensaad et al, 2006; Franklin et al, 2016; Liu et al, 2020; Ros et al, 2017)
In addition to its inhibition of Glucose-6-phosphate dehydrogenase (G6PD) and pentose phosphate pathway (PPP) that is important for DNA synthesis and lipid synthesis (Jiang, et al, 2011), p53 can transcriptionally upregulate aromatase that is involved in lipid metabolism (Wang et al, 2013)
Summary
Reprogramming of cellular metabolism is one of the “hallmarks of cancer”, and is considered one of the main driving forces for tumorigenesis (Hanahan and Weinberg, 2011). Numerous reports indicate that p53 is playing extensive and complex roles in regulating various metabolic pathways, and the gain of function mutants of p53 promotes the oncogenic metabolic reprogramming that induces drug resistance and metastasis. Numerous studies have shown that p53 plays complex roles in regulating glucose metabolism.
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