p53 and metabolism: from mechanism to therapeutics
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Fernando M. Simabuco1, Mirian G. Morale2,3, Isadora C.B. Pavan1, Ana P. Morelli1, Fernando R. Silva1 and Rodrigo E. Tamura4
1Laboratory of Functional Properties in Foods, School of Applied Sciences (FCA), Universidade de Campinas (UNICAMP), Limeira, São Paulo, Brazil
2Center for Translational Investigation in Oncology/LIM24, Instituto do Câncer do Estado de São Paulo (ICESP), São Paulo, Brazil
3Department of Radiology and Oncology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
4Universidade Federal de São Paulo, Departamento de Ciências Biólogicas, Diadema, SP, Brazil
Rodrigo E. Tamura, email: [email protected]
Keywords: metabolism; p53; mutant p53; chemotherapy; drug resistance
Received: February 12, 2018 Accepted: April 06, 2018 Published: May 04, 2018
The tumor cell changes itself and its microenvironment to adapt to different situations, including action of drugs and other agents targeting tumor control. Therefore, metabolism plays an important role in the activation of survival mechanisms to keep the cell proliferative potential. The Warburg effect directs the cellular metabolism towards an aerobic glycolytic pathway, despite the fact that it generates less adenosine triphosphate than oxidative phosphorylation; because it creates the building blocks necessary for cell proliferation. The transcription factor p53 is the master tumor suppressor; it binds to more than 4,000 sites in the genome and regulates the expression of more than 500 genes. Among these genes are important regulators of metabolism, affecting glucose, lipids and amino acids metabolism, oxidative phosphorylation, reactive oxygen species (ROS) generation and growth factors signaling. Wild-type and mutant p53 may have opposing effects in the expression of these metabolic genes. Therefore, depending on the p53 status of the cell, drugs that target metabolism may have different outcomes and metabolism may modulate drug resistance. Conversely, induction of p53 expression may regulate differently the tumor cell metabolism, inducing senescence, autophagy and apoptosis, which are dependent on the regulation of the PI3K/AKT/mTOR pathway and/or ROS induction. The interplay between p53 and metabolism is essential in the decision of cell fate and for cancer therapeutics.
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