Cancer-Associated, Interdependent Regulation of mTOR, AKT, and IKK/NF-kappaB

Summary

Principal Investigator: ALBERT SIDNEY BALDWIN
Abstract: DESCRIPTION (provided by applicant): Akt is widely activated in a variety of cancers via (i) mutation in the PTEN tumor suppressor, (ii) activating mutations in PI3K, and (ii) through growth factor receptor upregulation/stimulation. Promotion of oncogenic mechanisms downstream of Akt involve stimulation of cellular proliferation and survival through phosphorylation of key substrates. For example, Akt is known to phosphorylate TSC2 to upregulate mTOR, to phosphorylate and inactivate pro-apoptotic Forkhead proteins, and to activate the transcription factor NF-kB (which functions in cell proliferation and survival). A key effector of the Akt pathway is mTOR, itself a kinase that functions in the TORC1 complex. Importantly, Akt is required for the development and progression of several animal models of cancer, and inhibition of mTOR with rapamycin blocks tumor growth induced by Akt. Additionally, a distinct mTOR complex (TORC2) containing the protein Rictor has been demonstrated to be the PDK2 activity that controls Akt activation via phosphorylation on ser473. Rapamycin, which blocks mTOR activity, has shown efficacy in certain cancers, but has failed in others due to a loss of a negative feedback pathway on IRS-1 and Akt activation. Thus, it is of extreme importance to understand potential regulatory mechanisms that could control both mTOR and Akt activation in cancers. We have published that IKK?, an upstream regulator of NF-kB pathway which is associated with oncogenesis, controls TORC1 activity in PTEN-null/inactive prostate cancers. A recently published paper from our group demonstrates that this interaction, reciprocally, leads to an mTOR/Raptor-dependent control of NF-kB activation controlling the expression of anti-apoptotic genes. Additionally, our preliminary data shows that IKK? associates with the TORC2 complex in PC3 prostate cancer cells to control Akt S473 phosphorylation and kinase activity. Thus, IKK? functions to regulate mTOR activity in both TORC1 and TORC2, raising the potential that IKK? inhibition could function to inhibit both TORC1 and TORC2, circumventing problems associated with rapamycin and its effects on feedback control of Akt activation. We propose to: (i) characterize mechanisms whereby IKK? controls TORC2 activity, determining if a specific IKK? inhibitor will block both TORC1 and TORC2 activity, (ii) determine if IKK??inhibition is cytotoxic/cytostatic in cancer cells and if this will block the loss of feedback control on IRS-1/Akt, and (iii) determine if genetic and pharmacologic inhibition of IKK? and/or IKK? will block progression and development of cancer in a PTEN-loss model of prostate cancer. As a human correlate, studies will be performed on primary human glioblastoma explants. The studies may identify a single mechanism to suppress mTOR and Akt activity in cancer. The studies are also the first to use a specific IKK? inhibitor for cancer studies.
Funding Period: 1998-04-01 - 2014-01-31
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 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
  3. 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
  4. 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
  5. pmc Oncogenic EGFR signaling activates an mTORC2-NF-κB pathway that promotes chemotherapy resistance
    Kazuhiro Tanaka
    Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at the University of California, Los Angeles, CA 90095, USA
    Cancer Discov 1:524-38. 2011
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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

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 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...
  3. 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...
  4. 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...
  5. pmc Oncogenic EGFR signaling activates an mTORC2-NF-κB pathway that promotes chemotherapy resistance
    Kazuhiro Tanaka
    Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at the University of California, Los Angeles, CA 90095, USA
    Cancer Discov 1:524-38. 2011
    ..These findings suggest that therapeutic strategies targeting mTORC2, alone or in combination with chemotherapy, will be effective in the treatment of cancer...
  6. 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...
  7. 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...
  8. 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...
  9. 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. ..
  10. 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...
  11. pmc Deletion of the NF-κB subunit p65/RelA in the hematopoietic compartment leads to defects in hematopoietic stem cell function
    Sarah J Stein
    Department of Biology, University of North Carolina, Chapel Hill, NC 27599, USA
    Blood 121:5015-24. 2013
    ..These studies demonstrate that p65 is an important regulator of hematopoiesis through the transcription of genes involved in HSC fate...
  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 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...
  14. 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...
  15. 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...
  16. 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...
  17. 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...
  18. 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...
  19. 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...
  20. 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...
  21. 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...
  22. ncbi Differential involvement of IkappaB kinases alpha and beta in cytokine- and insulin-induced mammalian target of rapamycin activation determined by Akt
    Han C Dan
    Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
    J Immunol 180:7582-9. 2008
    ..In MCF7 cells, TNF does not activate Akt and requires IKKbeta to activate mTOR. The results show that Akt-dependent signaling, induced by cytokines or insulin, alters the IKK subunit-dependent control of mTOR...
  23. 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...
  24. 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
    ....
  25. 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...
  26. 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...