Regulation of cancer cell metabolism

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Abstract

Interest in the topic of tumour metabolism has waxed and waned over the past century of cancer research. The early observations of Warburg and his contemporaries established that there are fundamental differences in the central metabolic pathways operating in malignant tissue. However, the initial hypotheses that were based on these observations proved inadequate to explain tumorigenesis, and the oncogene revolution pushed tumour metabolism to the margins of cancer research. In recent years, interest has been renewed as it has become clear that many of the signalling pathways that are affected by genetic mutations and the tumour microenvironment have a profound effect on core metabolism, making this topic once again one of the most intense areas of research in cancer biology.

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TIGAR, a p53-Inducible Regulator of Glycolysis and Apoptosis

Karim Bensaad, Atsushi Tsuruta, Mary A. Selak … (2006)

The p53 tumor-suppressor protein prevents cancer development through various mechanisms, including the induction of cell-cycle arrest, apoptosis, and the maintenance of genome stability. We have identified a p53-inducible gene named TIGAR (TP53-induced glycolysis and apoptosis regulator). TIGAR expression lowered fructose-2,6-bisphosphate levels in cells, resulting in an inhibition of glycolysis and an overall decrease in intracellular reactive oxygen species (ROS) levels. These functions of TIGAR correlated with an ability to protect cells from ROS-associated apoptosis, and consequently, knockdown of endogenous TIGAR expression sensitized cells to p53-induced death. Expression of TIGAR may therefore modulate the apoptotic response to p53, allowing survival in the face of mild or transient stress signals that may be reversed or repaired. The decrease of intracellular ROS levels in response to TIGAR may also play a role in the ability of p53 to protect from the accumulation of genomic damage.

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Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics.

G. L. Semenza (2010)

Adaptation of cancer cells to their microenvironment is an important driving force in the clonal selection that leads to invasive and metastatic disease. O2 concentrations are markedly reduced in many human cancers compared with normal tissue, and a major mechanism mediating adaptive responses to reduced O2 availability (hypoxia) is the regulation of transcription by hypoxia-inducible factor 1 (HIF-1). This review summarizes the current state of knowledge regarding the molecular mechanisms by which HIF-1 contributes to cancer progression, focusing on (1) clinical data associating increased HIF-1 levels with patient mortality; (2) preclinical data linking HIF-1 activity with tumor growth; (3) molecular data linking specific HIF-1 target gene products to critical aspects of cancer biology and (4) pharmacological data showing anticancer effects of HIF-1 inhibitors in mouse models of human cancer.

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AMP-activated protein kinase induces a p53-dependent metabolic checkpoint.

Russell G. Jones, David Plas, Sara Kubek … (2005)

Replicative cell division is an energetically demanding process that can be executed only if cells have sufficient metabolic resources to support a doubling of cell mass. Here we show that proliferating mammalian cells have a cell-cycle checkpoint that responds to glucose availability. The glucose-dependent checkpoint occurs at the G(1)/S boundary and is regulated by AMP-activated protein kinase (AMPK). This cell-cycle arrest occurs despite continued amino acid availability and active mTOR. AMPK activation induces phosphorylation of p53 on serine 15, and this phosphorylation is required to initiate AMPK-dependent cell-cycle arrest. AMPK-induced p53 activation promotes cellular survival in response to glucose deprivation, and cells that have undergone a p53-dependent metabolic arrest can rapidly reenter the cell cycle upon glucose restoration. However, persistent activation of AMPK leads to accelerated p53-dependent cellular senescence. Thus, AMPK is a cell-intrinsic regulator of the cell cycle that coordinates cellular proliferation with carbon source availability.

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Author and article information

Journal

Title: Nature Reviews Cancer

Abbreviated Title: Nat Rev Cancer

Publisher: Springer Science and Business Media LLC

ISSN (Print): 1474-175X

ISSN (Electronic): 1474-1768

Publication date Created: February 2011

Publication date (Electronic): January 24 2011

Publication date (Print): February 2011

Volume: 11

Issue: 2

Pages: 85-95

Article

DOI: 10.1038/nrc2981

PubMed ID: 21258394

SO-VID: 2fdec5a6-fac3-4960-91d8-90d8609ab19e

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http://www.springer.com/tdm

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Regulation of cancer cell metabolism

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Cancer Metabolism

Most cited references 76

TIGAR, a p53-Inducible Regulator of Glycolysis and Apoptosis

Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics.

AMP-activated protein kinase induces a p53-dependent metabolic checkpoint.

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