P53 as a Regulator of Lipid Metabolism in Cancer.

Alejandro Parrales,Tomoo Iwakuma

doi:10.3390/ijms17122074

Abstract

Enhanced proliferation and survival are common features of cancer cells. Cancer cells are metabolically reprogrammed which aids in their survival in nutrient-poor environments. Indeed, changes in metabolism of glucose and glutamine are essential for tumor progression. Thus, metabolic reprogramming is now well accepted as a hallmark of cancer. Recent findings suggest that reprogramming of lipid metabolism also occurs in cancer cells, since lipids are used for biosynthesis of membranes, post-translational modifications, second messengers for signal transduction, and as a source of energy during nutrient deprivation. The tumor suppressor p53 is a transcription factor that controls the expression of proteins involved in cell cycle arrest, DNA repair, apoptosis, and senescence. p53 also regulates cellular metabolism, which appears to play a key role in its tumor suppressive activities. In this review article, we summarize non-canonical functions of wild-type and mutant p53 on lipid metabolism and discuss their association with cancer progression.

Highlights

Cancer cells have an extraordinary ability to adapt themselves to adverse environments
We focus on lipid metabolism pathways that are directly associated with p53, including fatty acid synthesis, fatty acid oxidation, cholesterol synthesis, cholesterol efflux, and lipid droplet formation
Recent data from our laboratory have demonstrated that mevalonte-5-phosphate (MVP), an intermediate metabolite in the mevalonate pathway, is involved in the stabilization of conformational p53 mutants, since the inhibition of MVP production leads to the degradation of conformational mutant p53 [63]

Summary

Introduction

Cancer cells have an extraordinary ability to adapt themselves to adverse environments. Glutamine consumption is high in cancer cells, likely due to an increase in demand of carbon structures and amino-nitrogen which are required for nucleotide, protein, and lipid synthesis [4] Besides these changes in glucose and amino acid metabolism, fast-proliferating cancer cells have high avidity for lipids (fatty acids and cholesterol) which are mainly used for biosynthesis of structural components of the cells (membranes), as well as for production of energy during nutrient deprivation [5]. A wide variety of tumors have increased expression of acetyl-CoA-carboxylase (ACC) [6] that catalyzes the conversion of acetyl-CoA to malonyl-CoA, the rate-limiting step in the lipid biosynthesis [5] Another enzyme involved in lipid metabolism and highly overexpressed in cancers is fatty acid synthase (FAS), an enzyme that converts acetyl-CoA to palmitic acid [9]. We summarize studies that focus on the contributions of both wild-type and mutant p53 to lipid metabolism

Regulation of Lipid Metabolism by Wild-Type p53

Aromatase

Lipin 1

Caveolin 1

Roles of Mutant p53 in the Lipid Metabolism

Summary and Future Perspectives