Mitochondrial Metabolism and ROS Regulate Lung Cancer

Summary

Principal Investigator: Navdeep S Chandel
Abstract: DESCRIPTION (provided by applicant): Lung cancer is the most common cause of cancer-related death in both men and women in the United States. Eighty percent of lung cancers are non-small cell lung cancers (NSCLCs) and 30% of NSCLCs are adenocarcinomas, which include a rising population of cancer cases that occur in nonsmokers. Mutations in the Kras oncogene, which signals through a cascade of kinases to promote cellular proliferation, have been identified in 20-30% of NSCLCs. Therapeutic targeting of Kras-driven tumors necessitates the identification of signaling pathways required for oncogenic Kras-driven proliferation. Kras-driven lung cancer cells display higher levels of reactive oxygen species (ROS) than noncancerous lung cells. ROS have been proposed to serve as signaling molecules to activate numerous signaling pathways, including PI3K, ERK1/2 MAPK, and the transcription factors hypoxia inducible factors (HIFs), which promote tumor cell proliferation, angiogenesis, and metastasis. The major form of ROS that participates in signaling in the cytosol is hydrogen peroxide (H2O2), which is generated by its conversion from superoxide (O2-) by copper-zinc superoxide dismutase (SOD1) in the cytosol. We have reported that O2- from mitochondrial complex III and its conversion to H2O2 in the cytosol are required to initiate Kras-induced cellular proliferation and hypoxic activation of HIFs in tumor cells. Presently, it is not known whether complex III-generated O2- or H2O2-dependent signaling in the cytosol is required for oncogenic Kras-driven lung tumorigenicity in vivo. Recent studies indicate that glutamine is a major fuel for the TCA cycle to generate NADH and FADH2. These reducing equivalents donate electrons to the electron transport chain resulting in complex III generated superoxide. We recently reported that Kras-driven tumor cells also utilize glutamine to fuel the TCA cycle. Glutamine can be converted by glutaminase (GLS) to glutamate, which enters the TCA cycle through conversion into alpha-ketoglutarate by aminotransferases (GPT2 or GOT2) or glutamate dehydrogenase (GDH). Preliminary data indicate that preventing glutamine entry into the TCA cycle using inhibitors of aminotransferases or RNAi of GPT2 reduces anchorage-independent growth of oncogenic Kras-driven tumor cells. However, it is not known if inhibition of GPT2 would attenuate lung adenocarcinoma in vivo or if GPT2 is dispensable for normal tissues in the adult mouse. The major goal of this grant is to genetically determine whether diminishing complex III generated superoxide, production of cytosolic hydrogen peroxide, and glutamine utilization by the TCA cycle will attenuate tumorigenesis in the oncogenic Kras-driven mouse model of lung adenocarcinoma and in an orthotopic mouse model using human A549 lung adenocarcinoma cells harboring a Kras mutation.
Funding Period: 2006-07-01 - 2017-05-31
more information: NIH RePORT

Top Publications

  1. pmc The Qo site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production
    Eric L Bell
    Department of Medicine, Northwestern University Medical School, Chicago, IL 60611, USA
    J Cell Biol 177:1029-36. 2007
  2. pmc Mitochondrial complex III: an essential component of universal oxygen sensing machinery?
    Navdeep S Chandel
    Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Medical School, Chicago, IL 60611, USA
    Respir Physiol Neurobiol 174:175-81. 2010
  3. pmc Hypoxia. 2. Hypoxia regulates cellular metabolism
    William W Wheaton
    Division of Pulmonary and Critical Care Medicine, 240 East Huron Ave, McGraw M 334, Chicago, IL 60611 2909, USA
    Am J Physiol Cell Physiol 300:C385-93. 2011
  4. pmc Hypoxia leads to Na,K-ATPase downregulation via Ca(2+) release-activated Ca(2+) channels and AMPK activation
    Galina A Gusarova
    Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
    Mol Cell Biol 31:3546-56. 2011
  5. pmc NF-κB controls energy homeostasis and metabolic adaptation by upregulating mitochondrial respiration
    Claudio Mauro
    Section of Inflammation and Signal Transduction, Department of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
    Nat Cell Biol 13:1272-9. 2011
  6. pmc Reductive carboxylation supports growth in tumour cells with defective mitochondria
    Andrew R Mullen
    Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390 9063, USA
    Nature 481:385-8. 2012
  7. pmc The role of nuclear lamin B1 in cell proliferation and senescence
    Takeshi Shimi
    Department of Cell and Molecular Biology, Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA
    Genes Dev 25:2579-93. 2011
  8. pmc Targeting glucose metabolism for cancer therapy
    Robert B Hamanaka
    Division of Pulmonary and Critical Care, Department of Medicine, Northwestern University Medical School, Chicago, IL 60611, USA
    J Exp Med 209:211-5. 2012
  9. pmc Physiological roles of mitochondrial reactive oxygen species
    Laura A Sena
    Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
    Mol Cell 48:158-67. 2012
  10. pmc The proto-oncometabolite fumarate binds glutathione to amplify ROS-dependent signaling
    Lucas B Sullivan
    Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
    Mol Cell 51:236-48. 2013

Detail Information

Publications27

  1. pmc The Qo site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production
    Eric L Bell
    Department of Medicine, Northwestern University Medical School, Chicago, IL 60611, USA
    J Cell Biol 177:1029-36. 2007
    ..These results provide genetic and pharmacologic evidence that the Qo site of complex III is required for the transduction of hypoxic signal by releasing ROS to stabilize the HIF-1alpha protein...
  2. pmc Mitochondrial complex III: an essential component of universal oxygen sensing machinery?
    Navdeep S Chandel
    Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Medical School, Chicago, IL 60611, USA
    Respir Physiol Neurobiol 174:175-81. 2010
    ..Here I propose a model wherein complex III is integral to oxygen sensing in regulating diverse response to hypoxia...
  3. pmc Hypoxia. 2. Hypoxia regulates cellular metabolism
    William W Wheaton
    Division of Pulmonary and Critical Care Medicine, 240 East Huron Ave, McGraw M 334, Chicago, IL 60611 2909, USA
    Am J Physiol Cell Physiol 300:C385-93. 2011
    ..In this review, we discuss these mechanisms that diminish metabolic supply and demand for adaptation to hypoxia...
  4. pmc Hypoxia leads to Na,K-ATPase downregulation via Ca(2+) release-activated Ca(2+) channels and AMPK activation
    Galina A Gusarova
    Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
    Mol Cell Biol 31:3546-56. 2011
    ..These data suggest that during hypoxia, calcium entry via CRAC channels leads to AMPK activation, Na,K-ATPase downregulation, and alveolar epithelial dysfunction...
  5. pmc NF-κB controls energy homeostasis and metabolic adaptation by upregulating mitochondrial respiration
    Claudio Mauro
    Section of Inflammation and Signal Transduction, Department of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
    Nat Cell Biol 13:1272-9. 2011
    ..Our findings identify NF-κB as a physiological regulator of mitochondrial respiration and establish a role for NF-κB in metabolic adaptation in normal cells and cancer...
  6. pmc Reductive carboxylation supports growth in tumour cells with defective mitochondria
    Andrew R Mullen
    Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390 9063, USA
    Nature 481:385-8. 2012
    ....
  7. pmc The role of nuclear lamin B1 in cell proliferation and senescence
    Takeshi Shimi
    Department of Cell and Molecular Biology, Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA
    Genes Dev 25:2579-93. 2011
    ..This overexpression eventually leads to cell cycle arrest at the G1/S boundary. These results demonstrate the importance of LB1 in regulating the proliferation and senescence of human diploid cells through a ROS signaling pathway...
  8. pmc Targeting glucose metabolism for cancer therapy
    Robert B Hamanaka
    Division of Pulmonary and Critical Care, Department of Medicine, Northwestern University Medical School, Chicago, IL 60611, USA
    J Exp Med 209:211-5. 2012
    ..It is anticipated that understanding which metabolic enzymes are particularly critical for tumor cell proliferation and survival will identify novel therapeutic targets...
  9. pmc Physiological roles of mitochondrial reactive oxygen species
    Laura A Sena
    Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
    Mol Cell 48:158-67. 2012
    ..More and more evidence suggests that mROS are critical for healthy cell function. In this Review, we discuss this evidence following some background on the generation and regulation of mROS...
  10. pmc The proto-oncometabolite fumarate binds glutathione to amplify ROS-dependent signaling
    Lucas B Sullivan
    Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
    Mol Cell 51:236-48. 2013
    ..Increased ROS also correlates with hypermethylation of histones in these cells. Thus, fumarate serves as a proto-oncometabolite by binding to glutathione which results in the accumulation of ROS...
  11. pmc Targeting SOD1 reduces experimental non-small-cell lung cancer
    Andrea Glasauer
    J Clin Invest . 2013
    ....
  12. pmc Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes
    Robert B Hamanaka
    Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Medical School, Chicago, IL 60611, USA
    Trends Biochem Sci 35:505-13. 2010
    ....
  13. pmc Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity
    Frank Weinberg
    Division of Pulmonary and Critical Care, Department of Medicine, Robert H Lurie Comprehensive Cancer Center, Northwestern University Medical School Chicago, IL 60611, USA
    Proc Natl Acad Sci U S A 107:8788-93. 2010
    ..These results demonstrate that mitochondrial metabolism and mitochondrial ROS generation are essential for Kras-induced cell proliferation and tumorigenesis...
  14. pmc Inter-connection between mitochondria and HIFs
    Kathryn V Tormos
    Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Medical School, Chicago, IL 60611 2909, USA
    J Cell Mol Med 14:795-804. 2010
    ..In this review, we examine the evidence that mitochondria and HIFs are intimately connected to regulate each other resulting in appropriate responses to hypoxia...
  15. pmc Compound C inhibits hypoxic activation of HIF-1 independent of AMPK
    Brooke M Emerling
    Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA
    FEBS Lett 581:5727-31. 2007
    ..Furthermore, we demonstrate that Compound C functions as a repressor of HIF-1 by inhibiting respiration and suppressing mitochondrial generated ROS...
  16. pmc A chemical genomics screen highlights the essential role of mitochondria in HIF-1 regulation
    Xiaoyu Lin
    Cancer Research and Advanced Technology, Global Pharmaceutical Research and Development, AP10, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA
    Proc Natl Acad Sci U S A 105:174-9. 2008
    ..These results also suggest that targeting mitochondrial ROS production might be a highly effective way of blocking HIF-1 activity in tumors...
  17. ncbi Mitochondrial complex III regulates hypoxic activation of HIF
    T Klimova
    Department of Medicine, Northwestern University Medical School, Chicago, IL 60611, USA
    Cell Death Differ 15:660-6. 2008
    ..This review examines the current knowledge about the role of mitochondrial ROS in HIF activation, as well as implications of ROS-level regulation in pathological processes such as cancer...
  18. pmc PTEN regulates p300-dependent hypoxia-inducible factor 1 transcriptional activity through Forkhead transcription factor 3a (FOXO3a)
    Brooke M Emerling
    Department of Medicine, Northwestern University Medical School, Chicago, IL 60611, USA
    Proc Natl Acad Sci U S A 105:2622-7. 2008
    ..Coimmunoprecipitation and GAL4-HIF-1alpha transactivation assays reveal that FOXO3a interferes with p300-dependent HIF-1 transcriptional activity. Thus, FOXO3a negatively regulates HIF-1 transcriptional activity...
  19. pmc Hypoxic activation of AMPK is dependent on mitochondrial ROS but independent of an increase in AMP/ATP ratio
    Brooke M Emerling
    Department of Medicine, Northwestern University Medical School, Chicago, IL 60611, USA
    Free Radic Biol Med 46:1386-91. 2009
    ..Collectively, these data indicate that oxidative stress and not an increase in the AMP/ATP ratio is required for hypoxic activation of AMPK...
  20. pmc Mitochondrial regulation of cell survival and death during low-oxygen conditions
    Colleen M Snyder
    Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Medical School, Chicago, Illinois, USA
    Antioxid Redox Signal 11:2673-83. 2009
    ..5-3% O2), mitochondrial oxidative stress activates hypoxia-inducible factors (HIFs) to promote cell survival. In this review, we discuss how mitochondria, BCL-2 proteins, and HIFs are crucial for cellular responses to low oxygen...
  21. ncbi Reactive oxygen species-dependent signaling regulates cancer
    Frank Weinberg
    Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Medical School, Chicago, IL 60611, USA
    Cell Mol Life Sci 66:3663-73. 2009
    ..Here we review the role of redox-dependent signaling pathways and transcription factors that regulate tumorigenesis...
  22. pmc Nitric oxide induces cell death by regulating anti-apoptotic BCL-2 family members
    Colleen M Snyder
    Department of Medicine, Northwestern University Medical School, Chicago, Illinois, United States of America
    PLoS ONE 4:e7059. 2009
    ..However, scavengers of ROS or peroxynitrite do not prevent NO-induced cell death. Collectively, these data indicate that NO degrades MCL-1 through the ASK1-JNK1 axis to induce BAX/BAK-dependent cell death...
  23. pmc Mitochondrial reactive oxygen species regulate hypoxic signaling
    Robert B Hamanaka
    Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Medical School, Chicago, IL 60611, USA
    Curr Opin Cell Biol 21:894-9. 2009
    ..The following is a brief overview of the current understanding of the role of mitochondrial-produced ROS in cellular oxygen signaling...
  24. ncbi Mitochondrial metabolism and cancer
    Frank Weinberg
    Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Medical School, Chicago, IL 60611 2010, USA
    Ann N Y Acad Sci 1177:66-73. 2009
    ..Here we review the accumulating evidence that mitochondrial metabolism plays an essential role in tumor cell proliferation...
  25. pmc Bim-Bcl-2 homology 3 mimetic therapy is effective at suppressing inflammatory arthritis through the activation of myeloid cell apoptosis
    John C Scatizzi
    St Louis University School of Medicine, St Louis, MO, USA
    Arthritis Rheum 62:441-51. 2010
    ....
  26. pmc ROS function in redox signaling and oxidative stress
    Michael Schieber
    Division of Pulmonary and Critical Care Medicine, Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
    Curr Biol 24:R453-62. 2014
    ..Here, we argue that redox biology, rather than oxidative stress, underlies physiological and pathological conditions...

Research Grants30

  1. Role of Id1 in NSCLC Progression and Metastasis
    Srikumar P Chellappan; Fiscal Year: 2013
    ..We believe that an in-depth mechanistic analysis as proposed in this application will lead to the development of novel therapeutic agents for non-small cell lungs cancer based on targeting the Id1 protein. ..
  2. PROTON RADIATION THERAPY RESEARCH
    Thomas F DeLaney; Fiscal Year: 2013
    ..abstract_text> ..
  3. Regulation of Tumorigenesis and therapeutic resistance by Nrf2 in lung cancer
    Shyam Biswal; Fiscal Year: 2013
    ..Successful completion of this project will develop a new therapeutic strategy for lung cancer treatment. ..
  4. Regulation of Tumor Metabolism by Retinoblastoma Protein
    Brian F Clem; Fiscal Year: 2013
    ..2. To determine the effects of Rb1 deletion on glucose/glutamine metabolism and growth of lung adenocarcinomas in vivo. 3. To correlate the loss of Rb function with changes in the 13C-glucose utilization by human lung tumors in vivo. ..
  5. Characterization and therapeutic targeting of HIF in LKB1 - deficient lung cancer
    William Y Kim; Fiscal Year: 2013
    ....
  6. Signaling and Metabolic Control in the Drosophila Eye
    Utpal Banerjee; Fiscal Year: 2013
    ..In AIM 3, the oncogenic influence on cellular metabolism and the molecular mechanism that causes a metabolic shift towards glycolysis will be investigated. ..
  7. Role of 11q23 Chromosome Abnormalities in the Causation of Acute Leukemia
    Carlo M Croce; Fiscal Year: 2013
    ..abstract_text> ..
  8. Targeting Glucose Metabolism in Cancer
    Sucheta Telang; Fiscal Year: 2013
    ..3. To examine the effect of PFKFB4 genomic deletion on growth and metabolism of ras-dependent tumors in vivo using a Cre-lox inducible mouse knockout of PFKFB4. ..
  9. Molecular Mechanisms of Prostate Cancer Chemoprevention by Apigenin
    Sanjay Gupta; Fiscal Year: 2013
    ....
  10. Mechanisms of GVHD
    Joseph H Antin; Fiscal Year: 2013
    ..Ultimately we envision an integrated genomic profile that will determine the type of GVHD prophylaxis that will be most effective. ..
  11. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
    ....
  12. Hyperpolarized NMR for Studies of Cancer Therapies Targeting the Warburg Effect
    AARON KEITH GRANT; Fiscal Year: 2013
    ..In addition, we will investigate the use of metabolic therapies in conjunction with cisplatin, and compare the utility of hyperpolarized NMR and FDG PET in assessing tumor response. ..