HIF-1 Regulates Cytochrome Oxidase Subunits to Optimize Efficiency of Respiration in Hypoxic Cells

Fukuda, Ryo; Zhang, Huafeng; Kim, Jung-whan; Shimoda, Larissa A.; Dang, Chi V.; Semenza, Gregg L.

doi:10.1016/j.cell.2007.01.047

Cited by 1,081 publications

(978 citation statements)

References 45 publications

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“…These changes include an increase in glycolytic enzyme expression and isoform selection, the diversion of pyruvate away from the mitochondrion (Kim et al, 2006;Papandreou et al, 2006) and alterations in the affinity of the electron transport chain (cytochrome c oxidase) to oxygen (Fukuda et al, 2007), all of which are HIF1a dependent. However, the publication of the PHD1 knockout mouse has also raised the possibility that reactivating PHD1 under hypoxia could have effects on cellular metabolism independently of HIF1a (Aragones et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Reactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death

et al. 2009

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Cells exposed to low-oxygen conditions (hypoxia) alter their metabolism to survive. This response, although vital during development and high-altitude survival, is now known to be a major factor in the selection of cells with a transformed metabolic phenotype during tumorigenesis. It is thought that hypoxia-selected cells have increased invasive capacity and resistance to both chemo-and radiotherapies, and therefore represent an attractive target for antitumor therapy. Hypoxia inducible factors (HIFs) are responsible for the majority of gene expression changes under hypoxia, and are themselves controlled by the oxygen-sensing HIF prolyl hydroxylases (PHDs). It was previously shown that mutations in succinate dehydrogenase lead to the inactivation PHDs under normoxic conditions, which can be overcome by treatment with a-ketoglutarate derivatives. Given that solid tumors contain large regions of hypoxia, the reactivation of PHDs in these conditions could induce metabolic catastrophe and therefore prove an effective antitumor therapy. In this report we demonstrate that derivatized a-ketoglutarate can be used as a strategy for maintaining PHD activity under hypoxia. By increasing intracellular a-ketoglutarate and activating PHDs we trigger PHD-dependent reversal of HIF1 activation, and PHD-dependent hypoxic cell death. We also show that derivatized a-ketoglutarate can permeate multiple layers of cells, reducing HIF1a levels and its target genes in vivo.

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Section: Discussionmentioning

confidence: 99%

Reactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death

et al. 2009

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“…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. Thereby, HIF not only channels glucose towards glycolysis by repressing mitochondrial respiration but it also optimizes low levels of respiration by regulating the ratio of isoforms of cytochrome c oxidase, components of the electron transport chain [29]. This strategy not only makes respiration more efficient but may also protect cells from oxidative damage under hypoxic conditions.…”

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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“…[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 Regulates Cytochrome Oxidase Subunits to Optimize Efficiency of Respiration in Hypoxic Cells

Cited by 1,081 publications

References 45 publications

Reactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death

Reactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death

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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