Tumor Necrosis Factor-Alpha Signaling in Breast Cancer

Summary

Principal Investigator: Alakananda Basu
Abstract: Apoptosis is a highly orchestrated cell suicidal program required to maintain a balance between cell proliferation and cell death. Tumor necrosis factor-a (TNF), a pleotropic cytokine, plays an important role in immunesurveillance. The interaction of TNF with its receptors triggers activation of a family of cysteine proteases or caspases that are essential for the execution of cell death by apoptosis. The ability to evade cell death pathway is a critical event in cancer progression. Various pro- and antiapoptotic signal transduction pathways regulate activation of caspases by TNF. Protein kinase C (PKC), a family of serine/threonine kinases, plays a critical role in growth factor signal transduction pathway. During our previous funding period, we have shown that novel PKC isozymes act as anti-apoptotic proteins to inhibit cell death by TNF. The abundance of novel PKCs, however, was not sufficient to explain cellular sensitivity/resistance to TNF. A deregulation in Akt/protein kinase B (PKB) signal transduction pathway has been associated with the genesis of several cancers, including breast cancer although the molecular mechanism(s) by which this signaling pathway contributes to breast cancer pathogenesis is incompletely understood. We hypothesize that the PKC signal transduction pathway cooperates with components of the phosphatidylinositol 3-kinase (PI3K) pathway, such as PKB to regulate cell survival and cell death. The overall objective of this grant proposal is to delineate how a deregulation in PI3K/PKB signaling pathway that exists in breast cancer cells influences anti-apoptotic signaling by PKC. The long-term objective is to develop strategies to intervene with these pathways to inhibit progression of breast cancer.
Funding Period: 2009-06-01 - 2009-10-31
more information: NIH RePORT

Top Publications

  1. pmc Novel regulation of protein kinase C-η
    Deepanwita Pal
    Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
    Biochem Biophys Res Commun 425:836-41. 2012
  2. pmc S6 kinase 2 promotes breast cancer cell survival via Akt
    Savitha Sridharan
    Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas, USA
    Cancer Res 71:2590-9. 2011
  3. ncbi Two faces of protein kinase Cδ: the contrasting roles of PKCδ in cell survival and cell death
    Alakananda Basu
    Department of Molecular Biology and Immunology, University of North Texas Health Science Center and Institute for Cancer Research, Fort Worth, TX, USA
    ScientificWorldJournal 10:2272-84. 2010
  4. ncbi PKCepsilon induces Bcl-2 by activating CREB
    Eswar Shankar
    Department of Molecular Biology and Immunology, University of North Texas Health Science Center and Institute for Cancer Research, Fort Worth, TX 76107, USA
    Int J Oncol 36:883-8. 2010
  5. pmc Regulation of protein kinase C delta downregulation by protein kinase C epsilon and mammalian target of rapamycin complex 2
    Alakananda Basu
    Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA
    Cell Signal 21:1680-5. 2009
  6. pmc Proteolytic cleavage of p70 ribosomal S6 kinase by caspase-3 during DNA damage-induced apoptosis
    Rohini Dhar
    Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA
    Biochemistry 48:1474-80. 2009
  7. ncbi Manipulation of PKC isozymes by RNA interference and inducible expression of PKC constructs
    Alakananda Basu
    Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas, USA
    Methods Enzymol 446:141-57. 2008
  8. ncbi Constitutive activation of p70 S6 kinase is associated with intrinsic resistance to cisplatin
    Rohini Dhar
    Department of Molecular Biology and Immunology, University of North Texas Health Science Center and Institute for Cancer Research, Fort Worth, TX 76107, USA
    Int J Oncol 32:1133-7. 2008
  9. ncbi Down-regulation of caspase-2 by rottlerin via protein kinase C-delta-independent pathway
    Alakananda Basu
    Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
    Cancer Res 68:2795-802. 2008
  10. ncbi Protein kinase C epsilon confers resistance of MCF-7 cells to TRAIL by Akt-dependent activation of Hdm2 and downregulation of p53
    E Shankar
    Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
    Oncogene 27:3957-66. 2008

Scientific Experts

  • Alakananda Basu
  • U Sivaprasad
  • Rohini Dhar
  • Dongmei Lu
  • Eswar Shankar
  • E Shankar
  • Deepanwita Pal
  • Savitha Sridharan
  • Jie Huang
  • Shalini Persaud Outram
  • Soumya Krishnamurthy
  • Rajiv Paranandi
  • Joe R Mireles
  • Shalini D Persaud
  • Usha Sivaprasad
  • Shavonda Morrow

Detail Information

Publications16

  1. pmc Novel regulation of protein kinase C-η
    Deepanwita Pal
    Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
    Biochem Biophys Res Commun 425:836-41. 2012
    ..Knockdown of PKCε but not PKCα inhibited PKC activator-induced upregulation of PKCη. Thus, our results suggest that the regulation of PKCη is unique and PKCε is required for the PKC activator-induced upregulation of PKCη...
  2. pmc S6 kinase 2 promotes breast cancer cell survival via Akt
    Savitha Sridharan
    Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas, USA
    Cancer Res 71:2590-9. 2011
    ..Taken together, our study shows that the two homologues of S6K have distinct effects on Akt activation and cell survival. Thus, targeting S6K2 may be an effective therapeutic strategy to treat cancers...
  3. ncbi Two faces of protein kinase Cδ: the contrasting roles of PKCδ in cell survival and cell death
    Alakananda Basu
    Department of Molecular Biology and Immunology, University of North Texas Health Science Center and Institute for Cancer Research, Fort Worth, TX, USA
    ScientificWorldJournal 10:2272-84. 2010
    ..This review discusses the current literature on the contrasting roles of PKCδ in cell survival and cell death...
  4. ncbi PKCepsilon induces Bcl-2 by activating CREB
    Eswar Shankar
    Department of Molecular Biology and Immunology, University of North Texas Health Science Center and Institute for Cancer Research, Fort Worth, TX 76107, USA
    Int J Oncol 36:883-8. 2010
    ..In addition, knockdown of CREB sensitized MDA-MB-231 cells to TRAIL-mediated cell death. These results suggest that PKCepsilon regulates Bcl-2 induction through activation of the transcription factor CREB...
  5. pmc Regulation of protein kinase C delta downregulation by protein kinase C epsilon and mammalian target of rapamycin complex 2
    Alakananda Basu
    Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA
    Cell Signal 21:1680-5. 2009
    ..Depletion of PKC epsilon also enhanced PKC delta downregulation by PDBu. These results suggest that downregulation of PKC delta is regulated by PKC epsilon and mammalian target of rapamycin complex 2 (mTORC2)...
  6. pmc Proteolytic cleavage of p70 ribosomal S6 kinase by caspase-3 during DNA damage-induced apoptosis
    Rohini Dhar
    Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA
    Biochemistry 48:1474-80. 2009
    ..These results suggest that p70S6K is a novel substrate for caspase-3 and that the proteolytic cleavage of p70S6K is important for cisplatin-induced apoptosis...
  7. ncbi Manipulation of PKC isozymes by RNA interference and inducible expression of PKC constructs
    Alakananda Basu
    Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas, USA
    Methods Enzymol 446:141-57. 2008
    ..In this chapter, we describe the use of RNA interference (siRNA) technology and tetracycline-inducible expression of PKC isozymes to study their function in apoptosis...
  8. ncbi Constitutive activation of p70 S6 kinase is associated with intrinsic resistance to cisplatin
    Rohini Dhar
    Department of Molecular Biology and Immunology, University of North Texas Health Science Center and Institute for Cancer Research, Fort Worth, TX 76107, USA
    Int J Oncol 32:1133-7. 2008
    ....
  9. ncbi Down-regulation of caspase-2 by rottlerin via protein kinase C-delta-independent pathway
    Alakananda Basu
    Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
    Cancer Res 68:2795-802. 2008
    ..Furthermore, down-regulation of caspase-2 by rottlerin can explain its antiapoptotic function during DNA damage-induced apoptosis...
  10. ncbi Protein kinase C epsilon confers resistance of MCF-7 cells to TRAIL by Akt-dependent activation of Hdm2 and downregulation of p53
    E Shankar
    Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
    Oncogene 27:3957-66. 2008
    ..These results suggest that PKC epsilon mediates TRAIL resistance by Akt-mediated phosphorylation of Hdm2 resulting in suppression of p53 expression and downregulation of Bid in MCF-7 breast cancer cells...
  11. ncbi Inhibition of ERK attenuates autophagy and potentiates tumour necrosis factor-alpha-induced cell death in MCF-7 cells
    U Sivaprasad
    Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
    J Cell Mol Med 12:1265-71. 2008
    ..These data suggest that TNF-induces autophagy through ERK1/2 and that inhibition of autophagy increases cellular sensitivity to TNF...
  12. ncbi Protein kinase C-epsilon protects MCF-7 cells from TNF-mediated cell death by inhibiting Bax translocation
    Dongmei Lu
    Department of Molecular Biology and Immunology, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA
    Apoptosis 12:1893-900. 2007
    ..PKCepsilon was coimmunoprecipitated with Bax in MCF-7 cells. These results suggest that PKCepsilon mediates its antiapoptotic effect partly by preventing activation and translocation of Bax to the mitochondria...
  13. pmc Protein kinase Cepsilon makes the life and death decision
    Alakananda Basu
    Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
    Cell Signal 19:1633-42. 2007
    ..We have also discussed how PKCepsilon mediates its antiapoptotic signal by altering the level or function of pro- and antiapoptotic Bcl-2 family members...
  14. ncbi Downregulation of Bid is associated with PKCepsilon-mediated TRAIL resistance
    U Sivaprasad
    Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
    Cell Death Differ 14:851-60. 2007
    ..Thus, our results suggest that PKCepsilon acts upstream of mitochondria and mediates TRAIL resistance via both Bcl-2 and Bid in MCF-7 cells...
  15. ncbi Protein kinase Cepsilon activates protein kinase B/Akt via DNA-PK to protect against tumor necrosis factor-alpha-induced cell death
    Dongmei Lu
    Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA
    J Biol Chem 281:22799-807. 2006
    ..These results suggest that PKCepsilon activates Akt via DNA-PK to mediate its antiapoptotic function. Furthermore, we report for the first time that DNA-PK can regulate receptor-initiated apoptosis via Akt...