Suppression of Peroxiredoxin 4 in Glioblastoma Cells Increases Apoptosis and Reduces Tumor Growth

Glioblastoma multiforme (GBM), the most common and aggressive primary brain malignancy, is incurable despite the best combination of current cancer therapies. For the development of more effective therapies, discovery of novel candidate tumor drivers is urgently needed. Here, we report that peroxiredoxin 4 (PRDX4) is a putative tumor driver. PRDX4 levels were highly increased in a majority of human GBMs as well as in a mouse model of GBM. Reducing PRDX4 expression significantly decreased GBM cell growth and radiation resistance in vitro with increased levels of ROS, DNA damage, and apoptosis. In a syngenic orthotopic transplantation model, Prdx4 knockdown limited GBM infiltration and significantly prolonged mouse survival. These data suggest that PRDX4 can be a novel target for GBM therapies in the future.

[1]  R. Sanz-Pamplona,et al.  Peroxiredoxin 2 specifically regulates the oxidative and metabolic stress response of human metastatic breast cancer cells in lungs , 2013, Oncogene.

[2]  K. Huh,et al.  Peroxiredoxin-2 upregulated by NF-κB attenuates oxidative stress during the differentiation of muscle-derived C2C12 cells. , 2012, Antioxidants & redox signaling.

[3]  J. Schulte.  Peroxiredoxin 4: a multifunctional biomarker worthy of further exploration , 2011, BMC medicine.

[4]  Chulhee Choi,et al.  Peroxiredoxin II is an essential antioxidant enzyme that prevents the oxidative inactivation of VEGF receptor-2 in vascular endothelial cells. , 2011, Molecular cell.

[5]  M. Pecaut,et al.  Comparison of proton and electron radiation effects on biological responses in liver, spleen and blood , 2011, International journal of radiation biology.

[6]  P. Mischel,et al.  CD44v6 Regulates Growth of Brain Tumor Stem Cells Partially through the AKT-Mediated Pathway , 2011, PloS one.

[7]  T. Golub,et al.  Selective killing of cancer cells with a small molecule targeting stress response to ROS , 2011, Nature.

[8]  T. Finkel,et al.  Signal transduction by reactive oxygen species , 2011, The Journal of cell biology.

[9]  J. Stamler,et al.  Glioma Stem Cell Proliferation and Tumor Growth Are Promoted by Nitric Oxide Synthase-2 , 2011, Cell.

[10]  R. Franco,et al.  Reactive oxygen species (ROS)--induced genetic and epigenetic alterations in human carcinogenesis. , 2011, Mutation research.

[11]  T. Veenstra,et al.  Sulfiredoxin–Peroxiredoxin IV axis promotes human lung cancer progression through modulation of specific phosphokinase signaling , 2011, Proceedings of the National Academy of Sciences.

[12]  D. Ron,et al.  Oxidative protein folding by an endoplasmic reticulum-localized peroxiredoxin. , 2010, Molecular cell.

[13]  J. Bartek,et al.  Replication stress and oxidative damage contribute to aberrant constitutive activation of DNA damage signalling in human gliomas , 2010, Oncogene.

[14]  N. Bulleid,et al.  Peroxiredoxin IV protects cells from oxidative stress by removing H2O2 produced during disulphide formation , 2010, Journal of Cell Science.

[15]  Yonghong Xiao,et al.  PLAGL2 regulates Wnt signaling to impede differentiation in neural stem cells and gliomas. , 2010, Cancer cell.

[16]  Michael R. Green,et al.  A genome-wide RNA interference screen reveals an essential CREB3L2/ATF5/MCL1 survival pathway in malignant glioma with therapeutic implications , 2010, Nature Medicine.

[17]  Peter G Schultz,et al.  An RNAi screen identifies TRRAP as a regulator of brain tumor-initiating cell differentiation. , 2010, Cell stem cell.

[18]  A. Álvarez-Buylla,et al.  Combinations of genetic mutations in the adult neural stem cell compartment determine brain tumour phenotypes , 2010, The EMBO journal.

[19]  Nicolò Riggi,et al.  EZH2 is essential for glioblastoma cancer stem cell maintenance. , 2009, Cancer research.

[20]  C. Brennan,et al.  Glioblastoma Subclasses Can Be Defined by Activity among Signal Transduction Pathways and Associated Genomic Alterations , 2009, PloS one.

[21]  Bao-qin Liu,et al.  TNF‐related apoptosis‐inducing ligand suppresses PRDX4 expression , 2009, FEBS letters.

[22]  David García-Dorado,et al.  TGF-beta increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma. , 2009, Cancer cell.

[23]  Madhuchhanda Bhattacharjee,et al.  Conserved gene expression programs integrate mammalian prostate development and tumorigenesis. , 2009, Cancer research.

[24]  C. Wan,et al.  Comparative Proteomic Analysis of Osteosarcoma Cell and Human Primary Cultured Osteoblastic Cell , 2009, Cancer investigation.

[25]  Zhen Gao,et al.  Late ROS accumulation and radiosensitivity in SOD1-overexpressing human glioma cells. , 2008, Free radical biology & medicine.

[26]  Gerald C. Chu,et al.  P53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation , 2008, Nature.

[27]  D. Spitz,et al.  Decreasing peroxiredoxin II expression decreases glutathione, alters cell cycle distribution, and sensitizes glioma cells to ionizing radiation and H(2)O(2). , 2008, Free radical biology & medicine.

[28]  P. Tsichlis,et al.  The JmjC Domain Histone Demethylase Ndy1 Regulates Redox Homeostasis and Protects Cells from Oxidative Stress , 2008, Molecular and Cellular Biology.

[29]  D. Busam,et al.  An Integrated Genomic Analysis of Human Glioblastoma Multiforme , 2008, Science.

[30]  Joshua M. Korn,et al.  Comprehensive genomic characterization defines human glioblastoma genes and core pathways , 2008, Nature.

[31]  R. Mason,et al.  Pten haploinsufficiency accelerates formation of high-grade astrocytomas. , 2008, Cancer research.

[32]  Byung-Gyu Kim,et al.  Proteomic profiling of endothelial cells in human lung cancer. , 2008, Journal of proteome research.

[33]  L. Chin,et al.  Malignant astrocytic glioma: genetics, biology, and paths to treatment. , 2007, Genes & development.

[34]  V. Martin,et al.  Signaling pathways involved in antioxidant control of glioma cell proliferation. , 2007, Free radical biology & medicine.

[35]  D. Spitz,et al.  Inhibiting catalase activity sensitizes 36B10 rat glioma cells to oxidative stress. , 2007, Free radical biology & medicine.

[36]  Thomas D. Wu,et al.  Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. , 2006, Cancer cell.

[37]  P. Chumakov,et al.  The antioxidant function of the p53 tumor suppressor , 2005, Nature Medicine.

[38]  D. Albertson,et al.  Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability , 2005, Nature.

[39]  Dae-Yeul Yu,et al.  Regulation of PDGF signalling and vascular remodelling by peroxiredoxin II , 2005, Nature.

[40]  Martin J. van den Bent,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[41]  C. Rhee,et al.  Increased expression of antioxidant enzymes in radioresistant variant from U251 human glioblastoma cell line. , 2004, International journal of molecular medicine.

[42]  S. Hilsenbeck,et al.  Somatic Mutation of p53 Leads to Estrogen Receptor α-Positive and -Negative Mouse Mammary Tumors with High Frequency of Metastasis , 2004, Cancer Research.

[43]  Yusuke Nakamura,et al.  Genes associated with liver metastasis of colon cancer, identified by genome-wide cDNA microarray. , 2004, International journal of oncology.

[44]  G. Jenkins,et al.  Detection of p53 mutations in precancerous gastric tissue , 2003, British Journal of Cancer.

[45]  A. Fisher,et al.  Induction of 1-cys peroxiredoxin expression by oxidative stress in lung epithelial cells. , 2003, American Journal of Physiology - Lung cellular and Molecular Physiology.

[46]  F. Klamt,et al.  Modulation of oxidative stress in response to gamma-radiation in human glioma cell lines , 2003, Journal of Neuro-Oncology.

[47]  G. Wahl,et al.  c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability. , 2002, Molecular cell.

[48]  A. Trumpp,et al.  Negative Regulation of Neural Stem/Progenitor Cell Proliferation by the Pten Tumor Suppressor Gene in Vivo , 2001, Science.

[49]  Eun Sug Park,et al.  Role of Peroxiredoxins in Regulating Intracellular Hydrogen Peroxide and Hydrogen Peroxide-induced Apoptosis in Thyroid Cells* , 2000, The Journal of Biological Chemistry.

[50]  E. Rogakou,et al.  DNA Double-stranded Breaks Induce Histone H2AX Phosphorylation on Serine 139* , 1998, The Journal of Biological Chemistry.

[51]  K. Jeang,et al.  Regulatory Role for a Novel Human Thioredoxin Peroxidase in NF-κB Activation* , 1997, The Journal of Biological Chemistry.

[52]  H. Armah.  Malignant Astrocytomas Originate from Neural Stem/Progenitor Cells in a Somatic Tumor Suppressor Mouse Model , 2010 .

[53]  C. Kwon.  Pten-Deficient Mouse Models for High-Grade Astrocytomas , 2009 .

[54]  K. Jeang,et al.  Regulatory role for a novel human thioredoxin peroxidase in NF-kappaB activation. , 1997, The Journal of biological chemistry.

[55]  H. Gaylord,et al.  AMERICAN ASSOCIATION FOR CANCER RESEARCH. , 1913, California state journal of medicine.