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Review
. 2020 Jan 3;12(1):124.
doi: 10.3390/cancers12010124.

Energy Metabolism in Cancer: The Roles of STAT3 and STAT5 in the Regulation of Metabolism-Related Genes

Arturo Valle-Mendiola  1 , Isabel Soto-Cruz  1
Affiliations
Review

Energy Metabolism in Cancer: The Roles of STAT3 and STAT5 in the Regulation of Metabolism-Related Genes

Arturo Valle-Mendiola et al. Cancers (Basel). .

Abstract

A central characteristic of many types of cancer is altered energy metabolism processes such as enhanced glucose uptake and glycolysis and decreased oxidative metabolism. The regulation of energy metabolism is an elaborate process involving regulatory proteins such as HIF (pro-metastatic protein), which reduces oxidative metabolism, and some other proteins such as tumour suppressors that promote oxidative phosphorylation. In recent years, it has been demonstrated that signal transducer and activator of transcription (STAT) proteins play a pivotal role in metabolism regulation. STAT3 and STAT5 are essential regulators of cytokine- or growth factor-induced cell survival and proliferation, as well as the crosstalk between STAT signalling and oxidative metabolism. Several reports suggest that the constitutive activation of STAT proteins promotes glycolysis through the transcriptional activation of hypoxia-inducible factors and therefore, the alteration of mitochondrial activity. It seems that STAT proteins function as an integrative centre for different growth and survival signals for energy and respiratory metabolism. This review summarises the functions of STAT3 and STAT5 in the regulation of some metabolism-related genes and the importance of oxygen in the tumour microenvironment to regulate cell metabolism, particularly in the metabolic pathways that are involved in energy production in cancer cells.

Keywords: HIF; STAT3; STAT5; Warburg effect; cancer metabolism; transcription factors.

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Conflict of interest statement

The authors report no conflict of interest. The authors alone are responsible for the content and writing of this manuscript.

Figures

Figure 1
Figure 1
General view of glycolysis. The main steps of the regulation of this pathway are the conversion of glucose to glucose-6-phosphate; fructose-6-phosphate to fructose 1, 6-biphosphate; and the formation of pyruvate from phosphoenolpyruvate. All glycolytic enzymes are deregulated in cancer.
Figure 2
Figure 2
General view of the pentose phosphate pathway. This pathway is parallel to glycolysis and is the main source of NADPH and pentoses. Its point of regulation is the conversion of glucose-6-phosphate to 6-phosphogluconolactone.
Figure 3
Figure 3
General view of the Krebs cycle. The regulation points are the condensation of oxaloacetate with acetyl-CoA, the conversion of D-isocitrate to α-ketoglutarate, and the conversion of this molecule to succinyl-CoA. Several enzymes of the tricarboxylic acid (TCA) cycle are deregulated in cancer. Several enzymes of the tricarboxylic acid (TCA) cycle are deregulated in cancer.
Figure 4
Figure 4
General view of the electron transport chain. This pathway is a series of five complexes transferring electrons from donors (NADH or FADH2) to acceptors (final acceptor is O2) and generates an electrochemical gradient which drives the synthesis of ATP.
Figure 5
Figure 5
JAK/STAT (signal transducer and activator of transcription) pathway. This pathway initiates with ligand binding (1), which induces receptor dimerisation, and the associated JAKs phosphorylate the receptors (2). STATs bind to the phosphorylated receptor (3). Subsequently, JAKs phosphorylate STATs (4). STATs separate from the receptor and dimerise (5) and then migrate to the nucleus (6A) or mitochondria (6B). STATs regulate gene expression in the nucleus (7).
Figure 6
Figure 6
Hypoxia-inducible factor (HIF) is a transcription factor and is expressed in all metazoan organisms. This factor is composed of two subunits: HIF-1α and HIF-1β. Under hypoxic conditions, HIF regulates the expression of hundreds of genes. In this figure, only the genes related to metabolism are shown.
See this image and copyright information in PMC

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