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      Hypoxia signaling pathways in cancer metabolism: the importance of co-selecting interconnected physiological pathways

      review-article
      Author(s): 1 ,   1 ,
      Publication date (Electronic):
      Journal: Cancer & Metabolism
      Publisher: BioMed Central
      Keywords: Hypoxia, HIF, Metabolism, Cancer

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          Abstract

          Both tumor hypoxia and dysregulated metabolism are classical features of cancer. Recent analyses have revealed complex interconnections between oncogenic activation, hypoxia signaling systems and metabolic pathways that are dysregulated in cancer. These studies have demonstrated that rather than responding simply to error signals arising from energy depletion or tumor hypoxia, metabolic and hypoxia signaling pathways are also directly connected to oncogenic signaling mechanisms at many points. This review will summarize current understanding of the role of hypoxia inducible factor (HIF) in these networks. It will also discuss the role of these interconnected pathways in generating the cancer phenotype; in particular, the implications of switching massive pathways that are physiologically 'hard-wired’ to oncogenic mechanisms driving cancer.

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          Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1.

          Weibo Luo, Hongxia Hu, Ryan Chang … (2011)
          The pyruvate kinase isoforms PKM1 and PKM2 are alternatively spliced products of the PKM2 gene. PKM2, but not PKM1, alters glucose metabolism in cancer cells and contributes to tumorigenesis by mechanisms that are not explained by its known biochemical activity. We show that PKM2 gene transcription is activated by hypoxia-inducible factor 1 (HIF-1). PKM2 interacts directly with the HIF-1α subunit and promotes transactivation of HIF-1 target genes by enhancing HIF-1 binding and p300 recruitment to hypoxia response elements, whereas PKM1 fails to regulate HIF-1 activity. Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1α and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells. Thus, PKM2 participates in a positive feedback loop that promotes HIF-1 transactivation and reprograms glucose metabolism in cancer cells. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia.

            Huafeng Zhang, Marta Bosch-Marce, Larissa Shimoda … (2008)
            Autophagy is a process by which cytoplasmic organelles can be catabolized either to remove defective structures or as a means of providing macromolecules for energy generation under conditions of nutrient starvation. In this study we demonstrate that mitochondrial autophagy is induced by hypoxia, that this process requires the hypoxia-dependent factor-1-dependent expression of BNIP3 and the constitutive expression of Beclin-1 and Atg5, and that in cells subjected to prolonged hypoxia, mitochondrial autophagy is an adaptive metabolic response which is necessary to prevent increased levels of reactive oxygen species and cell death.
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              A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation.

              G. L. Semenza, G. L. Wang (1992)
              We have identified a 50-nucleotide enhancer from the human erythropoietin gene 3'-flanking sequence which can mediate a sevenfold transcriptional induction in response to hypoxia when cloned 3' to a simian virus 40 promoter-chloramphenicol acetyltransferase reporter gene and transiently expressed in Hep3B cells. Nucleotides (nt) 1 to 33 of this sequence mediate sevenfold induction of reporter gene expression when present in two tandem copies compared with threefold induction when present in a single copy, suggesting that nt 34 to 50 bind a factor which amplifies the induction signal. DNase I footprinting demonstrated binding of a constitutive nuclear factor to nt 26 to 48. Mutagenesis studies revealed that nt 4 to 12 and 19 to 23 are essential for induction, as substitutions at either site eliminated hypoxia-induced expression. Electrophoretic mobility shift assays identified a nuclear factor which bound to a probe spanning nt 1 to 18 but not to a probe containing a mutation which eliminated enhancer function. Factor binding was induced by hypoxia, and its induction was sensitive to cycloheximide treatment. We have thus defined a functionally tripartite, 50-nt hypoxia-inducible enhancer which binds several nuclear factors, one of which is induced by hypoxia via de novo protein synthesis.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cancer Metab
                Journal ID (iso-abbrev): Cancer Metab
                Title: Cancer & Metabolism
                Publisher: BioMed Central
                ISSN (Electronic): 2049-3002
                Publication date Collection: 2014
                Publication date (Electronic): 4 February 2014
                Volume: 2
                Page: 3
                Affiliations
                [1 ]The Hypoxia Biology Laboratory, The Henry Wellcome Building for Molecular Physiology, The University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
                Article
                Publisher ID: 2049-3002-2-3
                DOI: 10.1186/2049-3002-2-3
                PMC ID: 3938304
                PubMed ID: 24491179
                SO-VID: c098ced9-34cc-44ff-a59b-bbdbb465619d
                Copyright © Copyright © 2014 Masson and Ratcliffe; licensee BioMed Central Ltd.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 20 September 2013
                Date accepted : 22 January 2014
                Categories
                Subject: Review

                Keywords: hypoxia,metabolism,hif,cancer
                Data availability:
                Keywords: hypoxia, metabolism, hif, cancer

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