Targeting Hypoxic Cells through the DNA Damage Response

Exposure to hypoxia-induced replication arrest initiates a DNA damage response that includes both ATR- and ATM-mediated signaling. DNA fiber analysis was used to show that these conditions lead to a replication arrest during both the initiation and elongation phases, and that this correlated with decreased levels of nucleotides. The DNA damage response induced by hypoxia is distinct from the classical pathways induced by damaging agents, primarily due to the lack of detectable DNA damage, but also due to the coincident repression of DNA repair in hypoxic conditions. The principle aims of the hypoxia-induced DNA damage response seem to be the induction of p53-dependent apoptosis or the preservation of replication fork integrity. The latter is of particular importance should reoxygenation occur. Tumor reoxygenation occurs as a result of spontaneous changes in blood flow and also therapy. Cells experiencing hypoxia and/or reoxygenation are, therefore, sensitive to loss or inhibition of components of the DNA damage response, including Chk1, ATM, ATR, and poly(ADP-ribose) polymerase (PARP). In addition, restoration of hypoxia-induced p53-mediated signaling may well be effective in the targeting of hypoxic cells. The DNA damage response is also induced in endothelial cells at moderate levels of hypoxia, which do not induce replication arrest. In this situation, phosphorylation of H2AX has been shown to be required for proliferation and angiogenesis and is, therefore, an attractive potential therapeutic target. Clin Cancer Res; 16(23); 5624–9. ©2010 AACR.

[1]  P. Okunieff,et al.  Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. , 1989, Cancer research.

[2]  M. Dewhirst,et al.  Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. , 1996, Cancer research.

[3]  David E. Housman,et al.  Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours , 1996, Nature.

[4]  P. Vaupel,et al.  Hypoxia and Radiation Response in Human Tumors. , 1996, Seminars in radiation oncology.

[5]  P Vaupel,et al.  Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. , 1996, Cancer research.

[6]  A. Giaccia,et al.  The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. , 1998, Cancer research.

[7]  P. Reichard,et al.  Ribonucleotide reductases. , 1998, Annual review of biochemistry.

[8]  J. Bussink,et al.  Changes in Blood Perfusion and Hypoxia after Irradiation of a Human Squamous Cell Carcinoma Xenograft Tumor Line , 2000, Radiation research.

[9]  S. Elledge,et al.  The DNA damage response: putting checkpoints in perspective , 2000, Nature.

[10]  A. Giaccia,et al.  Hypoxia Links ATR and p53 through Replication Arrest , 2002, Molecular and Cellular Biology.

[11]  A. Giaccia,et al.  ATR/ATM Targets Are Phosphorylated by ATR in Response to Hypoxia and ATM in Response to Reoxygenation* , 2003, The Journal of Biological Chemistry.

[12]  Stephen J. Elledge,et al.  Sensing DNA Damage Through ATRIP Recognition of RPA-ssDNA Complexes , 2003, Science.

[13]  W. El-Deiry.  The role of p53 in chemosensitivity and radiosensitivity , 2003, Oncogene.

[14]  M. Kastan,et al.  DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation , 2003, Nature.

[15]  Christopher J. Schofield,et al.  Oxygen sensing by HIF hydroxylases , 2004, Nature Reviews Molecular Cell Biology.

[16]  A. Giaccia,et al.  Inhibition of ATR Leads to Increased Sensitivity to Hypoxia/Reoxygenation , 2004, Cancer Research.

[17]  A. Giaccia,et al.  Hypoxic gene expression and metastasis , 2004, Cancer and Metastasis Reviews.

[18]  A. Harris,et al.  HIF-1α Induces Genetic Instability by Transcriptionally Downregulating MutSα Expression , 2005 .

[19]  P. Maxwell.  The HIF pathway in cancer. , 2005, Seminars in cell & developmental biology.

[20]  R. Jain.  Normalization of Tumor Vasculature: An Emerging Concept in Antiangiogenic Therapy , 2005, Science.

[21]  L. Ellis,et al.  Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  S. Gibson,et al.  Hypoxia-induced phosphorylation of Chk2 in an ataxia telangiectasia mutated-dependent manner. , 2005, Cancer research.

[23]  F. Kaper,et al.  Anoxia is necessary for tumor cell toxicity caused by a low-oxygen environment. , 2005, Cancer research.

[24]  A. Harris,et al.  HIF-1alpha induces genetic instability by transcriptionally downregulating MutSalpha expression. , 2005, Molecular cell.

[25]  Todd L Davidson,et al.  Hypoxic stress induces dimethylated histone H3 lysine 9 through histone methyltransferase G9a in mammalian cells. , 2006, Cancer research.

[26]  B. Wouters,et al.  “Translating” Tumor Hypoxia: Unfolded Protein Response (UPR)–Dependent and UPR-Independent Pathways , 2006, Molecular Cancer Research.

[27]  Alan Ashworth,et al.  Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. , 2006, Cancer research.

[28]  A. Giaccia,et al.  Checking in on Hypoxia/Reoxygenation , 2006, Cell cycle.

[29]  A. Giaccia,et al.  The roles of Chk 1 and Chk 2 in hypoxia and reoxygenation. , 2006, Cancer letters.

[30]  S. Welford,et al.  DNA Damage during Reoxygenation Elicits a Chk2-Dependent Checkpoint Response , 2006, Molecular and Cellular Biology.

[31]  Quynh-Thu Le,et al.  Lysyl oxidase is essential for hypoxia-induced metastasis , 2006, Nature.

[32]  S. Gibson,et al.  CHK2-Dependent Phosphorylation of BRCA1 in Hypoxia , 2006, Radiation research.

[33]  James L Tatum,et al.  Hypoxia: Importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy , 2006, International journal of radiation biology.

[34]  P. Jeggo,et al.  ATR‐dependent phosphorylation and activation of ATM in response to UV treatment or replication fork stalling , 2006, The EMBO journal.

[35]  Nicholas Denko,et al.  Overcoming Physiologic Barriers to Cancer Treatment by Molecularly Targeting the Tumor Microenvironment , 2006, Molecular Cancer Research.

[36]  M. Löbrich,et al.  Hyperthermia activates a subset of ataxia-telangiectasia mutated effectors independent of DNA strand breaks and heat shock protein 70 status. , 2007, Cancer research.

[37]  John D Gordan,et al.  HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. , 2007, Cancer cell.

[38]  G. Schwartz,et al.  Targeting Checkpoint Kinase 1 in Cancer Therapeutics , 2007, Clinical Cancer Research.

[39]  A. Harris,et al.  The Unfolded Protein Response and Integrated Stress Response to Anoxia , 2007, Clinical Cancer Research.

[40]  P. Glazer,et al.  Repression of RAD51 gene expression by E2F4/p130 complexes in hypoxia , 2007, Oncogene.

[41]  A. Giaccia,et al.  Oxygen sensing and the DNA-damage response. , 2007, Current opinion in cell biology.

[42]  Richard P. Hill,et al.  Hypoxia and metabolism: Hypoxia, DNA repair and genetic instability , 2008, Nature Reviews Cancer.

[43]  A. Giaccia,et al.  Hypoxic Conditions Atm Activation and Signaling Under , 2008 .

[44]  Mechthild Krause,et al.  A novel poly(ADP-ribose) polymerase inhibitor, ABT-888, radiosensitizes malignant human cell lines under hypoxia. , 2008, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[45]  Thomas Helleday,et al.  DNA repair pathways as targets for cancer therapy , 2008, Nature Reviews Cancer.

[46]  Gary Box,et al.  Small-Molecule Activation of p53 Blocks Hypoxia-Inducible Factor 1α and Vascular Endothelial Growth Factor Expression In Vivo and Leads to Tumor Cell Apoptosis in Normoxia and Hypoxia , 2009, Molecular and Cellular Biology.

[47]  R. McLendon,et al.  The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype , 2009, Cell cycle.

[48]  P. Ratcliffe,et al.  Angiogenesis: escape from hypoxia , 2009, Nature Medicine.

[49]  E. Rankin,et al.  Bringing H2AX into the angiogenesis family. , 2009, Cancer cell.

[50]  J. Pouysségur,et al.  HIF at a glance , 2009, Journal of Cell Science.

[51]  Mircea Ivan,et al.  MicroRNA regulation of DNA repair gene expression in hypoxic stress. , 2009, Cancer research.

[52]  James B. Mitchell,et al.  In Vitro and In Vivo Radiation Sensitization of Human Tumor Cells by a Novel Checkpoint Kinase Inhibitor , 2009 .

[53]  J. Bartek,et al.  The DNA-damage response in human biology and disease , 2009, Nature.

[54]  A. Nussenzweig,et al.  Histone H2AX is integral to hypoxia-driven neovascularization , 2009, Nature Medicine.

[55]  A. Harris,et al.  Effects of acute versus chronic hypoxia on DNA damage responses and genomic instability. , 2010, Cancer research.

[56]  R. Jain,et al.  Biomarkers of antiangiogenic therapy: how do we move from candidate biomarkers to valid biomarkers? , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[57]  Edward S. Kim,et al.  Distinct patterns of cytokine and angiogenic factor modulation and markers of benefit for vandetanib and/or chemotherapy in patients with non-small-cell lung cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[58]  Y. Pommier,et al.  Chk1 inhibition after replicative stress activates a double strand break response mediated by ATM and DNA-dependent protein kinase , 2010, Cell cycle.

[59]  Yun Dai,et al.  New Insights into Checkpoint Kinase 1 in the DNA Damage Response Signaling Network , 2010, Clinical Cancer Research.

[60]  James B. Mitchell,et al.  In vitro and In vivo Radiation Sensitization of Human Tumor Cells by a Novel Checkpoint Kinase Inhibitor, AZD7762 , 2010, Clinical Cancer Research.

[61]  E. Di Gennaro,et al.  Restoring p53 function in cancer: novel therapeutic approaches for applying the brakes to tumorigenesis. , 2010, Recent patents on anti-cancer drug discovery.

[62]  Jonathan Maybaum,et al.  Mechanism of radiosensitization by the Chk1/2 inhibitor AZD7762 involves abrogation of the G2 checkpoint and inhibition of homologous recombinational DNA repair. , 2010, Cancer research.