title: Upregulation of PKCη by PKCε and PDK1 involves two distinct mechanisms and promotes breast cancer cell survival.
abstract: BACKGROUND
  Protein kinase C (PKC) serves as the receptor for tumor-promoting phorbol esters, which are potent activators of conventional (c) and novel (n) PKCs. We recently showed that these activators induced selective upregulation of PKCη in breast cancer cells. The objective of this study is to understand unique regulation of PKCη and its importance in breast cancer.
  
  
  METHODS
  The levels of PKC isozymes were monitored in breast cancer cells following treatment with inhibitors of kinases, proteasome and proteases by Western blotting. PKCε was introduced by adenoviral delivery. PKCη and PDK1 were depleted by siRNA silencing. Cell growth was determined by the MTT or clonal assay.
  
  
  RESULTS
  The general PKC inhibitors Gö 6983 and bisindolylmaleimide but not cPKC inhibitor Gö 6976 led to substantial PKCη downregulation, which was partly rescued by the introduction of nPKCε. Inhibition of phosphoinositide-dependent kinase-1 (PDK1) by Ly294002 or knockdown of PDK1 also led to downregulation of basal PKCη but had no effect on PKC activator-induced upregulation of PKCη. Proteasome inhibitors blocked PKCη downregulation triggered by PDK1 inhibition/depletion but not by Gö 6983. PKCη level increased in malignant but not in non-tumorigenic or pre-malignant cells in the progressive MCF-10A series associated with activated PDK1, and knockdown of PKCη inhibited breast cancer cell growth and clonogenic survival.
  
  
  CONCLUSIONS
  Upregulation of PKCη contributes to breast cancer cell growth and targeting either PKCε or PDK1 triggers PKCη downregulation but involves two distinct mechanisms.
  
  
  CONCLUSIONS
  The status of PKCη may serve as a potential biomarker for breast cancer malignancy.
authors.affiliation: Department of Molecular Biology & Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
authors.forename: Deepanwita
authors.initials: D
authors.lastname: Pal
authors.forename: Shalini Persaud
authors.initials: SP
authors.lastname: Outram
authors.forename: Alakananda
authors.initials: A
authors.lastname: Basu
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D001943:Breast Neoplasms / Q000209:etiology* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival; D002867:Chromones / Q000494:pharmacology; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology*; D051744:Protein Kinase C-epsilon / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D064413:3-Phosphoinositide-Dependent Protein Kinases; D002867:Chromones; D007211:Indoles; D008301:Maleimides; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D017346:Protein Serine-Threonine Kinases; C465664:2-(1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl)-3-(1H-indol-3-yl)maleimide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C081975:protein kinase C eta; C578562:PDPK1 protein, human
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