HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption

Papandreou, Ioanna; Cairns, Rob A.; Fontana, Lucrezia; Lim, Ai Lin; Denko, Nicholas C.

doi:10.1016/j.cmet.2006.01.012

Cited by 1,963 publications

(1,703 citation statements)

References 42 publications

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“…The expression of LDHA, another glycolytic gene best known to be responsive to HIF-1a or c-Myc, is not further enhanced by the two. Consistent with previous reports that the PDK1 gene is a target of HIF-1a, 54,55 c-Myc augments PKD1 expression in the presence of HIF-1a for lactate production. In addition, HIF1a and c-Myc also cooperate to activate the VEGFA gene.…”

Section: In C-myc-deregulated Cells Hif-1a Cooperates With C-myc To supporting

confidence: 92%

Carrot and stick: HIF-α engages c-Myc in hypoxic adaptation

Huang

2008

Cell Death Differ

124

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The past decade of research on hypoxic responses has provided a considerable understanding of how cells respond to hypoxic stress at the molecular level, thanks to the identification and molecular cloning of the hypoxia-inducible transcription factor, HIF-1a. Numerous target genes have since been identified to account for various aspects of the hypoxic response, including angiogenesis and glycolysis. Yet, fundamental questions remain regarding the mechanisms by which hypoxia controls cell proliferation, genetic instability, mitochondrial biogenesis, and oxidative respiration in cancer cells. Although the protooncoprotein c-Myc appears to be the diametrical opposite of HIF-1a in most of these processes, recent studies indicate that c-Myc is an integral part of the HIF-a-c-Myc molecular pathway in the hypoxic response. It has been shown that HIF-a engages with Myc by various mechanisms to achieve oxygen homeostasis for cell survival. This article focuses on the intricate roles of cMyc in the hypoxic response, discusses various mechanisms controlling c-Myc activity by HIF-a for the regulation of hypoxiaresponsive genes, and emphasizing the outcome of gene expression apparently dependent upon hypoxic conditions, cellular context, and gene promoter. Solid tumors tend to develop hypoxia (oxygen deprivation), which arises out of the rapid cell proliferation that outstrips the supply of oxygen from the blood vessels. Consequently, tumor hypoxia activates hypoxia-inducible factor (HIF)-1a and HIF-2a, 1,2 two of the well-characterized hypoxia-inducible transcription factors critical for tumor angiogenesis, glycolysis, and metastasis. [3][4][5] Under physiological conditions, hypoxia activates the ubiquitous HIF-1a, whereas HIF-2a expression is more tissue specific. Yet in human cancers of diverse origins, both HIF-1a and HIF-2a, referred to collectively hereinafter as HIF-a, are frequently overexpressed and activated.Hypoxia-inducible factor-a is the regulatory subunit of the HIF heterodimeric complex paired with the aryl hydrocarbon receptor nuclear translocator (ARNT, also known as HIF-1b). 6 They belong to the Per-ARNT-Sim (PAS) superfamily 7 of transcription factors containing basic helix-loop-helix domains (Figure 1a). Whereas PAS domains confer target gene specificity through protein-protein interactions, 8 the oxygendependent degradation domain, unique to HIF-a, mediates oxygen-dependent proteolysis. 9 As such, despite constitutive transcription and translation of the HIF1A and EPAS1 genes (encoding HIF-1a and HIF-2a, respectively), HIF-a protein levels remain low in oxygenated conditions because of proteolysis via the ubiquitin-proteasome pathway. 9-12 HIF-a degradation requires the pVHL-containing E3 ubiquitin ligase, 13-15 which recognizes two hydroxylated proline residues of HIF-a (P402 and P564 in HIF-1a; Figure 1a). [16][17][18] HIFa is hydroxylated by three prolyl hydroxylases, EglN1, EglN2, and EglN3 (better known as PHD2, PHD1, and PHD3, respectively), which sense oxygen tension and transduce oxygen signal...

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Section: In C-myc-deregulated Cells Hif-1a Cooperates With C-myc To supporting

confidence: 92%

Carrot and stick: HIF-α engages c-Myc in hypoxic adaptation

Huang

2008

Cell Death Differ

124

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“…This is made possible through an increase in HIF-mediated expression of both glucose transporters and enzymes of the glycolytic pathway, giving tumours a "glycolytic" phenotype. Diversion of pyruvate toward lactate and away from OXPHOS is also promoted through increased HIF-mediated expression of two key enzymes; lactate dehydrogenase A (LDH-A) [26] and pyruvate dehydrogenase kinase 1 (PDK1) [27,28]. LDH-A is the enzyme responsible for conversion of pyruvate to lactate, and PDK1 is an inhibitor of pyruvate dehydrogenase that feeds pyruvate into the tricarboxylic acid cycle and thus toward OXPHOS.…”

Section: Metabolismmentioning

confidence: 99%

Hypoxia and cancer

2007

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A major feature of solid tumours is hypoxia, decreased availability of oxygen, which increases patient treatment resistance and favours tumour progression. How hypoxic conditions are generated in tumour tissues and how cells respond to hypoxia are essential questions in understanding tumour progression and metastasis. Massive tumour-cell proliferation distances cells from the vasculature, leading to a deficiency in the local environment of blood carrying oxygen and nutrients. Such hypoxic conditions induce a molecular response, in both normal and neoplastic cells, that drives the activation of a key transcription factor; the hypoxia-inducible factor. This transcription factor regulates a large panel of genes that are exploited by tumour cells for survival, resistance to treatment and escape from a nutrient-deprived environment. Although now recognized as a major contributor to cancer progression and to treatment failure, the precise role of hypoxia signalling in cancer and in prognosis still needs to be further defined. It is hoped that a better understanding of the mechanisms implicated will lead to alternative and more efficient therapeutic approaches.

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“…Both HIF subtypes were simultaneously inhibited, as HIF-1 and HIF-2 share common target genes 6 including GLUT-1, 21,22 which was employed siRNA-targeting lung cancer in vivo F Kamlah et al to lactate by LDH-A. [24][25][26] At the mitochondrial level, pyruvate uptake is attenuated and mitochondrial respiration at complex IV is optimized for hypoxic conditions. 24,25,27 The overall increase in ATP generation by glycolysis directs metabolism in favor of tumor cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…[24][25][26] At the mitochondrial level, pyruvate uptake is attenuated and mitochondrial respiration at complex IV is optimized for hypoxic conditions. 24,25,27 The overall increase in ATP generation by glycolysis directs metabolism in favor of tumor cell proliferation. At the paracrine level, HIF induces various siRNA-targeting lung cancer in vivogrowth factor and receptor systems (for example, VEGF, VEGFR2, angiopoetins and ephrins), which initiate and maintain angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Intravenous injection of siRNA directed against hypoxia-inducible factors prolongs survival in a Lewis lung carcinoma cancer model

Kamlah

Eul

et al. 2008

Cancer Gene Ther

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Different routes for the in vivo administration of synthetic siRNA complexes targeting lung tumors were compared, and siRNA complexes were administered for the inhibition of hypoxia-inducible factor (HIF-1a and HIF-2a). Intravenous jugular vein injection of siRNA proved to be the most effective means of targeting lung tumor tissue in the Lewis lung carcinoma (LLC1) model. In comparison, intraperitoneal injection of siRNA was not suitable for targeting of lung tumor and intratracheal administration of siRNA exclusively targeted macrophages. Inhibition of HIF-1a and HIF-2a by siRNA injected intravenously was validated by immunohistofluorescent analysis for glucose-transporter-1 (GLUT-1), a well-established HIF target protein. The GLUT-1 signal was strongly attenuated in the lung tumors of mice treated with siRNA-targeting HIF-1a and HIF-2a, compared with mice treated with control siRNA. Interestingly, injection of siRNA directed against HIF-1a and HIF-2a into LLC1 lung tumor-bearing mice resulted in prolonged survival. Immunohistological analysis of the lung tumors from mice treated with siRNA directed against HIF-1a and HIF2a displayed reduced proliferation, angiogenesis and apoptosis, cellular responses, which are known to be affected by HIF. In conclusion, intravenous jugular vein injection of siRNA strongly targets the lung tumor and is effective in gene inhibition as demonstrated for HIF-1a and HIF-2a.

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HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption

Cited by 1,963 publications

References 42 publications

Carrot and stick: HIF-α engages c-Myc in hypoxic adaptation

Carrot and stick: HIF-α engages c-Myc in hypoxic adaptation

Hypoxia and cancer

Intravenous injection of siRNA directed against hypoxia-inducible factors prolongs survival in a Lewis lung carcinoma cancer model

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