Ras-Induced Lung Cancer: Key Roles for IKK and NF-kappaB

Summary

Principal Investigator: ALBERT SIDNEY BALDWIN
Abstract: DESCRIPTION (provided by applicant): Oncogenic mutations in Ras proteins lead to transforming potential in a number of epithelial cells. Unfortunately, the ability to suppress the Ras-driven signaling pathway in tumors, to date, has largely been unsuccessful. We originally showed that the transcription factor NF-?B is important for Ras-induced cell transformation through its ability to suppress Ras-induced cell death. In the first in vivo test for a role of NF-?B in oncogene-induced tumorigenesis, we show here that loss of the gene encoding the RelA/p65 NF-?B subunit suppresses Ras-induced tumorigenesis in a lung tumor model. Importantly, loss of RelA/p65 leads to apoptosis in these Ras-transformed cells. In vitro data indicate that IKKa and [unreadable], upstream regulators of NF-?B, and Aurora kinase control the ability of oncogenic Ras mutants to activate NF-?B. Additional new data indicate that variant forms of IKK, namely TBK1 and IKKe, nuclear in human lung tumor cells and that a dominant negative form of IKKe blocks NF-kB activation in these cells. Work from Counter and colleagues shows that the PI3K/Akt pathway is critical for tumor maintenance in a Ras-induced setting. We provide preliminary data that IKKa, in a manner distinct from its ability to control NF-?B activation, promotes Akt activity in cancer cells through regulation of the TORC2 complex. Due to the poor prognosis of many lung cancer patients and the hope for improved therapy of lung cancer, we have focused this proposal on K-Ras-induced lung tumorigenesis. The central hypotheses of this application are that: (1) a critical downstream effector of oncogenic K-Ras in lung cancer is the transcription factor NF-?B, (2) NF-?B activation induced by K-Ras involves therapeutic targets: Aurora kinases and I?B kinase a and [unreadable] (IKK[unreadable]), and potentially TBK1/IKKe and GSK-a/[unreadable];(3) therapies targeting IKK or Aurora kinase, and potentially GSK-a/[unreadable] will suppress tumor growth. Four specific aims are proposed to test these hypotheses. The proposed research may provide an experimental foundation leading to new treatments for Ras-positive tumors and will provide insight into molecular signaling events that are dysregulated downstream of mutant Ras expression. PUBLIC HEALTH RELEVANCE: While transforming mutations in Ras proteins occur widely in a number of cancers, the ability to suppress the pro-oncogenic effects of these proteins has largely failed. We originally showed that the transcription factor NF-?B is important for the ability of oncogenic to Ras to efficiently transform cells. Here we explore the importance of the NF-?B and IKK proteins in controlling K- Ras-induced lung tumorigenesis and lung tumor maintenance, using both genetically engineered animal models and pharmacologic inhibitors. In parallel, we explore molecular mechanisms whereby NF-?B and IKK function to promote oncogenic conversion and tumor maintenance. The proposed experiments have the potential to identify new targetable signaling pathways for treatment of Ras-expressing tumors, including those of the lung.
Funding Period: 1998-08-15 - 2015-01-31
more information: NIH RePORT

Top Publications

  1. pmc Expression of the Bcl-3 proto-oncogene suppresses p53 activation
    David Kashatus
    Curriculum in Genetics and Molecular Biology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA
    Genes Dev 20:225-35. 2006
  2. pmc Her2 activates NF-kappaB and induces invasion through the canonical pathway involving IKKalpha
    E C Merkhofer
    Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
    Oncogene 29:1238-48. 2010
  3. pmc IKKalpha and IKKbeta each function to regulate NF-kappaB activation in the TNF-induced/canonical pathway
    Mazhar Adli
    Department of Biology, University of North Carolina, Chapel Hill, North Carolina, United States of America
    PLoS ONE 5:e9428. 2010
  4. pmc Requirement of the NF-kappaB subunit p65/RelA for K-Ras-induced lung tumorigenesis
    Daniela S Bassères
    Lineberger Comprehensive Cancer Center and Department of Biology, University of North Carolina, Chapel Hill, North Carolina, USA
    Cancer Res 70:3537-46. 2010
  5. pmc IKK-dependent, NF-κB-independent control of autophagic gene expression
    W C Comb
    Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
    Oncogene 30:1727-32. 2011
  6. pmc NF-κB suppresses ROS levels in BCR-ABL(+) cells to prevent activation of JNK and cell death
    S J Stein
    Lineberger Comprehensive Cancer Center, Department of Biology, University of North Carolina, Chapel Hill, NC 27599, USA
    Oncogene 30:4557-66. 2011
  7. pmc p85α SH2 domain phosphorylation by IKK promotes feedback inhibition of PI3K and Akt in response to cellular starvation
    William C Comb
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
    Mol Cell 45:719-30. 2012
  8. pmc Oncogenic PI3K mutations lead to NF-κB-dependent cytokine expression following growth factor deprivation
    Jessica E Hutti
    Lineberger Comprehensive Cancer Center, Department of Biology, University of North Carolina at Chapel Hill, North Carolina 27599, USA
    Cancer Res 72:3260-9. 2012
  9. pmc Development of a high-throughput assay for identifying inhibitors of TBK1 and IKKε
    Jessica E Hutti
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina, United States of America
    PLoS ONE 7:e41494. 2012
  10. ncbi Canonical and non-canonical NF-κB signaling promotes breast cancer tumor-initiating cells
    M F Kendellen
    Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA
    Oncogene 33:1297-305. 2014

Detail Information

Publications27

  1. pmc Expression of the Bcl-3 proto-oncogene suppresses p53 activation
    David Kashatus
    Curriculum in Genetics and Molecular Biology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA
    Genes Dev 20:225-35. 2006
    ....
  2. pmc Her2 activates NF-kappaB and induces invasion through the canonical pathway involving IKKalpha
    E C Merkhofer
    Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
    Oncogene 29:1238-48. 2010
    ..In addition this work indicates the importance of IKKalpha as a mediator of Her2-induced tumor progression...
  3. pmc IKKalpha and IKKbeta each function to regulate NF-kappaB activation in the TNF-induced/canonical pathway
    Mazhar Adli
    Department of Biology, University of North Carolina, Chapel Hill, North Carolina, United States of America
    PLoS ONE 5:e9428. 2010
    ..These conclusions have led to a focus on development of IKKbeta inhibitors for potential use in inflammatory disorders and cancer...
  4. pmc Requirement of the NF-kappaB subunit p65/RelA for K-Ras-induced lung tumorigenesis
    Daniela S Bassères
    Lineberger Comprehensive Cancer Center and Department of Biology, University of North Carolina, Chapel Hill, North Carolina, USA
    Cancer Res 70:3537-46. 2010
    ..Taken together, these results show the importance of the NF-kappaB subunit p65/RelA in K-Ras-induced lung transformation and identify IKKbeta as a potential therapeutic target for K-Ras-induced lung cancer...
  5. pmc IKK-dependent, NF-κB-independent control of autophagic gene expression
    W C Comb
    Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
    Oncogene 30:1727-32. 2011
    ..Thus, IKK likely has multiple roles in response to starvation by regulating NF-κB-dependent antiapoptotic gene expression as well as controlling expression of autophagic genes through a yet undetermined mechanism...
  6. pmc NF-κB suppresses ROS levels in BCR-ABL(+) cells to prevent activation of JNK and cell death
    S J Stein
    Lineberger Comprehensive Cancer Center, Department of Biology, University of North Carolina, Chapel Hill, NC 27599, USA
    Oncogene 30:4557-66. 2011
    ..The data demonstrate that one function for NF-κB in oncogenesis is the suppression of oncoprotein-induced ROS levels and that inhibition of NF-κB in some cancers, including CML, will increase ROS levels and promote cell death...
  7. pmc p85α SH2 domain phosphorylation by IKK promotes feedback inhibition of PI3K and Akt in response to cellular starvation
    William C Comb
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
    Mol Cell 45:719-30. 2012
    ..Finally, leucine deprivation is shown to be necessary and sufficient for starvation-induced, IKK-mediated p85 phosphorylation and PI3K feedback inhibition...
  8. pmc Oncogenic PI3K mutations lead to NF-κB-dependent cytokine expression following growth factor deprivation
    Jessica E Hutti
    Lineberger Comprehensive Cancer Center, Department of Biology, University of North Carolina at Chapel Hill, North Carolina 27599, USA
    Cancer Res 72:3260-9. 2012
    ..These data also indicate that NF-κB plays diverse roles downstream from different oncogenic signaling pathways...
  9. pmc Development of a high-throughput assay for identifying inhibitors of TBK1 and IKKε
    Jessica E Hutti
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina, United States of America
    PLoS ONE 7:e41494. 2012
    ..Together, these data describe a new high-throughput screening assay which will facilitate the discovery of small molecule TBK1/IKKε inhibitors possessing therapeutic potential for both inflammatory diseases and cancer...
  10. ncbi Canonical and non-canonical NF-κB signaling promotes breast cancer tumor-initiating cells
    M F Kendellen
    Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA
    Oncogene 33:1297-305. 2014
    ..The results suggest the use of NF-κB inhibitors for clinical therapy of certain breast cancers. ..
  11. pmc GSK-3α promotes oncogenic KRAS function in pancreatic cancer via TAK1-TAB stabilization and regulation of noncanonical NF-κB
    Deepali Bang
    Department of Cell and Developmental Biology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
    Cancer Discov 3:690-703. 2013
    ..These data identify GSK-3α as a key downstream effector of oncogenic KRAS via its ability to coordinately regulate distinct NF-κB signaling pathways...
  12. pmc Application of multiplexed kinase inhibitor beads to study kinome adaptations in drug-resistant leukemia
    Matthew J Cooper
    Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America
    PLoS ONE 8:e66755. 2013
    ..These results demonstrate the utility of MIB/MS as a tool to identify dysregulated kinases and to interrogate kinome dynamics as cells respond to targeted kinase inhibition. ..
  13. pmc Addressing reported pro-apoptotic functions of NF-kappaB: targeted inhibition of canonical NF-kappaB enhances the apoptotic effects of doxorubicin
    Brian K Bednarski
    Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA
    PLoS ONE 4:e6992. 2009
    ..Therefore, combination therapies incorporating NF-kappaB inhibitors together with standard chemotherapies remains a viable method to improve the clinical outcomes in patients with advanced stage malignancies...
  14. pmc Maintenance of constitutive IkappaB kinase activity by glycogen synthase kinase-3alpha/beta in pancreatic cancer
    Willie Wilson
    Lineberger Comprehensive Cancer Center, Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina, USA 27599 7295
    Cancer Res 68:8156-63. 2008
    ..These data provide new insight into GSK-3-dependent NF-kappaB regulation and further establish GSK-3 and IKK as potential therapeutic targets for pancreatic cancer...
  15. ncbi NF-kappaB pathways in the immune system: control of the germinal center reaction
    Christine A Goetz
    Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, 405 West Dr, Room 213, Chapel Hill, NC 27599, USA
    Immunol Res 41:233-47. 2008
    ..We discuss potential mechanisms of action for Bcl-3 and Bcl-6 in this highly complex, but important process of B-cell affinity maturation...
  16. ncbi The kinases MSK1 and MSK2 are required for epidermal growth factor-induced, but not tumor necrosis factor-induced, histone H3 Ser10 phosphorylation
    Elizabeth A Duncan
    Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill 27599, USA
    J Biol Chem 281:12521-5. 2006
    ..These studies demonstrate the existence of pathway-specific mechanisms to control histone H3-Ser10 phosphorylation and gene expression...
  17. ncbi IKK-i/IKKepsilon controls constitutive, cancer cell-associated NF-kappaB activity via regulation of Ser-536 p65/RelA phosphorylation
    Mazhar Adli
    Lineberger Comprehensive Cancer Center, Department of Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA
    J Biol Chem 281:26976-84. 2006
    ..The data indicate a role for IKK-i/IKKepsilon in controlling proliferation of certain cancer cells through regulation of constitutive NF-kappaB activity...
  18. ncbi Regulation of mammalian target of rapamycin activity in PTEN-inactive prostate cancer cells by I kappa B kinase alpha
    Han C Dan
    Lineberger Comprehensive Cancer Center, Department of Biology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA
    Cancer Res 67:6263-9. 2007
    ..The results indicate a novel role for IKK alpha in controlling mTOR function in cancer cells with constitutive Akt activity...
  19. ncbi LZAP, a putative tumor suppressor, selectively inhibits NF-kappaB
    Jialiang Wang
    Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
    Cancer Cell 12:239-51. 2007
    ..In aggregate, these data support a role of LZAP in NF-kappaB regulation and tumor suppression...
  20. ncbi Expression of nuclear factor-kappaB family proteins in hepatocellular carcinomas
    BERT H O'NEIL
    Department of Medicine, Division of Hematology and Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
    Oncology 72:97-104. 2007
    ..Recent information has implicated IkappaB family members (e.g. Bcl-3) as possible mediators of NF-kappaB activation. Therefore, we examined the expression of all NF-kappaB family members and downstream targets in HCC...
  21. pmc Retinoic acid modulates chromatin to potentiate tumor necrosis factor alpha signaling on the DIF2 promoter
    Michael Witcher
    Lady Davis Institute for Medical Research, Segal Cancer Centre of the SMBD Jewish General Hospital, McGill University, Montreal H3T1E2, Quebec, Canada
    Nucleic Acids Res 36:435-43. 2008
    ....
  22. ncbi IkappaB kinase beta inhibition induces cell death in Imatinib-resistant and T315I Dasatinib-resistant BCR-ABL+ cells
    Elizabeth A Duncan
    Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599 7295, USA
    Mol Cancer Ther 7:391-7. 2008
    ..These data indicate that blockage of BCR-ABL-induced NF-kappaB activation via IkappaB kinase beta inhibition represents a potential new approach for treatment of Imatinib- or Dasatinib-resistant forms of chronic myelogenous leukemia...
  23. ncbi Loss of epithelial RelA results in deregulated intestinal proliferative/apoptotic homeostasis and susceptibility to inflammation
    Kris A Steinbrecher
    Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children s Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA
    J Immunol 180:2588-99. 2008
    ..We conclude that activation of RelA is required for homeostatic regulation of cell death and division in intestinal epithelia, as well as for protection from development of severe, acute inflammation of the intestine...
  24. pmc Akt-dependent regulation of NF-{kappa}B is controlled by mTOR and Raptor in association with IKK
    Han C Dan
    Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA
    Genes Dev 22:1490-500. 2008
    ..The results provide insight into the effects of Akt/mTOR-dependent signaling on gene expression and into the therapeutic action of rapamycin...
  25. pmc Essential role for epidermal growth factor receptor in glutamate receptor signaling to NF-kappaB
    Raquel Sitcheran
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 7295, USA
    Mol Cell Biol 28:5061-70. 2008
    ....
  26. pmc Active roles for inhibitory kappaB kinases alpha and beta in nuclear factor-kappaB-mediated chemoresistance to doxorubicin
    Brian K Bednarski
    Lineberger Comprehensive Cancer Center and Department of Surgery, University of North Carolina at Chapel Hill, 3010 Old Clinic Building, CB 7213, Chapel Hill, NC 27599 7213, USA
    Mol Cancer Ther 7:1827-35. 2008
    ..Moreover, we show that IKKalpha plays a critical role in NF-kappaB-mediated chemoresistance in response to doxorubicin and may serve as a potential target in combinational strategies to improve chemotherapeutic response...

Research Grants30

  1. Investigating the role of p73 and its isoforms in tumorigenesis and metastasis
    Elsa R Flores; Fiscal Year: 2013
    ..These studies will unveil the functions of the p73 isoforms in tumorigenesis and metastasis and have important clinical implication for patients with mutations in the p53/p73 pathway. ..
  2. Automatic Three Dimensional (3D) Registration for Enhanced Cancer Management
    CHARLES RAYMOND MEYER; Fiscal Year: 2013
    ..Generalized techniques that support controlling and optimizing these tradeoffs during dynamic imaging in MRI are very important. ..