Abstract
In order to meet the high energy demand, a metabolic reprogramming occurs in cancer cells. Its role is crucial in promoting tumor survival. Among the substrates in demand, oxygen is fundamental for bioenergetics. Nevertheless, tumor microenvironment is frequently characterized by low-oxygen conditions. Hypoxia-inducible factor 1 (HIF-1) is a pivotal modulator of the metabolic reprogramming which takes place in hypoxic cancer cells. In the hub of cellular bioenergetics, mitochondria are key players in regulating cellular energy. Therefore, a close crosstalk between mitochondria and HIF-1 underlies the metabolic and functional changes of cancer cells. Noteworthy, HIF-1 represents a promising target for novel cancer therapeutics. In this review, we summarize the molecular mechanisms underlying the interplay between HIF-1 and energetic metabolism, with a focus on mitochondria, of hypoxic cancer cells.
Highlights
Cells need appropriate oxygen (O2 ) concentration to allow aerobic respiration, and in turn, to produce ATP, the energetic fuel used in a large number of biological processes
It is known that tricarboxylic acid (TCA) cycle plays a dual role as a producer of NADH and FADH2, which fuel the mitochondrial electron transport chain to generate ATP, and as a supplier of metabolic intermediates required for anabolic reactions
Reducing the mitochondrial Complex I activity via NDUFA4L2 is an essential process in the mitochondrial reprogramming induced by Hypoxia-inducible factor 1 (HIF-1) that leads to a reduction of intracellular reactive oxygen species (ROS) production and preservation of membrane potential (Figure 3)
Summary
Three members of the HIF family have been identified. They all consist in a heterodimeric structure composed by an O2 -sensitive α subunit (HIF-1α, HIF-2α, and HIF-3α) and an O2 -insensitive β subunit (HIF-1β), known as aryl hydrocarbon receptor nuclear translocator (ARNT) [11]. The basic regions upstream of the N-terminal of the HLH domain of both HIF-1α and HIF-1β subunits mediate the binding to the HRE of target gene promoters (Figure 1) [12]. HIF-1β subunit lacks the ODD and the N-TAD domains but contains C-TAD alone (Figure 1) This structural difference reflects the function of subunits. HIF-1α is responsible for transcriptional activity since it contains the transactivation domains, whereas HIF-1β is only the dimerization partner and is not needed for the induction [15]. Experimental evidence shows that, under hypoxia, it is exproteasomal pathway Another HIF-1α hydroxylation reaction occurs in well-oxygenated pressed in adult mice thymus, lung, brain, kidneyHIF-1. In the oxygenated form, HIF-1 recognizes the von Hippel-Lindau tumor suppressor protein, which binds ubiquitin-conjugated E2 component to assemble the protein complex for the degradation by the ubiquitin-proteasomal pathway.
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