Hypoxia and metabolic adaptation of cancer cells

Abstract

Low oxygen tension (hypoxia) is a pervasive physiological and pathophysiological stimulus that metazoan organisms have contended with since they evolved from their single-celled ancestors. The effect of hypoxia on a tissue can be either positive or negative, depending on the severity, duration and context. Over the long-term, hypoxia is not usually consistent with normal function and so multicellular organisms have had to evolve both systemic and cellular responses to hypoxia. Our reliance on oxygen for efficient adenosine triphosphate (ATP) generation has meant that the cellular metabolic network is particularly sensitive to alterations in oxygen tension. Metabolic changes in response to hypoxia are elicited through both direct mechanisms, such as the reduction in ATP generation by oxidative phosphorylation or inhibition of fatty-acid desaturation, and indirect mechanisms including changes in isozyme expression through hypoxia-responsive transcription factor activity. Significant regions of cancers often grow in hypoxic conditions owing to the lack of a functional vasculature. As hypoxic tumour areas contain some of the most malignant cells, it is important that we understand the role metabolism has in keeping these cells alive. This review will outline our current understanding of many of the hypoxia-induced changes in cancer cell metabolism, how they are affected by other genetic defects often present in cancers, and how these metabolic alterations support the malignant hypoxic phenotype.

Figure 1

Decreasing oxygen tension elicits alterations in metabolism through a number of mechanisms. The direct effects of oxygen tension on metabolism are shown within the ‘oxygenation wedge', whereas those that are affected through signalling pathways activated in hypoxia are shown below. ALDH4, aldehyde dehydrogenase 4; GLUT1, facultative glucose transporter 1; HIF, hypoxia-inducible factor; HK2, hexokinase 2; LDHA, lactate dehydrogenase A; MAX, Myc-associated protein X; MCT4, monocarboxylate transporter 4; mROS, mitochondrial reactive oxygen species; MYC, V-Myc Avian Myelocytomatosis Viral Oncogene Homologue; NRF2, nuclear factor erythroid 2-related factor 2; OXPHOS, oxidative phosphorylation; PDK1, pyruvate dehydrogenase kinase 1; PGAM, phosphoglycerate mutase.

Figure 2

Some of the metabolic pathways known to have altered flux or importance in hypoxia. Metabolic pathways described in the text are shown, as are the enzymes mentioned, shown in red. Thicker lines represent those pathways in which hypoxic cells have been shown to increase flux, or rely more on their activity. αKG, alpha-ketoglutarate; 3PG, 3-phosphoglycerate; 6PGD, 6-phosphogluconate dehydrogenase; AcCoA, acetyl-Coenzyme A; ACO1/2, aconitase 1/2; ALD, aldolase; Asp, aspartate; Cit, citrate; CPS, cytidine triphosphate synthetase; Fum, fumarate; G3P, glyceraldehyde 3-phosphate; G6P, glucose 6-phosphate; G6PD, glucose 6-phosphate dehydrogenase; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; Glu, glutamate; GLS, glutaminase; Gly, glycine; GPAT, glutamine phosphoribosylpyrophosphate amidotransferase; GYS, glycogen synthase; HK, hexokinase; IDH1/2, isocitrate dehydrogenase 1/2; LDH, lactate dehydrogenase; Mal, malate; ME, malic enzyme; OAA, oxaloacetate; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; PDK1, pyruvate dehydrogenase kinase 1; PGAM, phosphoglycerate mutase; PYGL, glycogen phosphorylase; Pyr, pyruvate; Ser, serine; Suc, succinate.