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PMID: 20228845 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

Protein kinase Cvarepsilon mediates Stat3Ser727 phosphorylation, Stat3-regulated gene expression, and cell invasion in various human cancer cell lines through integration with MAPK cascade (RAF-1, MEK1/2, and ERK1/2).

Oncogene ·Vol. 29 ·No. 21 ·2010-05-27 ·Pages 3100-9

Aziz MH, Hafeez BB, Sand JM, Pierce DB, Aziz SW, Dreckschmidt NE, Verma AK

Abstract

Protein kinase C epsilon (PKCvarepsilon), a novel calcium-independent PKC isoform, has been shown to be a transforming oncogene. PKCvarepsilon-mediated oncogenic activity is linked to its ability to promote cell survival. However, the mechanisms by which PKCvarepsilon signals cell survival remain elusive. We found that signal transducers and activators of transcription 3 (Stat3), which is constitutively activated in a wide variety of human cancers, is a protein partner of PKCvarepsilon. Stat3 has two conserved amino-acid (Tyr705 and Ser727) residues, which are phosphorylated during Stat3 activation. PKCvarepsilon interacts with Stat3alpha isoform, which has Ser727, and not with Stat3beta isoform, which lacks Ser727. PKCvarepsilon-Stat3 interaction and Stat3Ser727 phosphorylation was initially observed during induction of squamous cell carcinomas and in prostate cancer. Now we present that (1) PKCvarepsilon physically interacts with Stat3alpha isoform in various human cancer cells: skin melanomas (MeWo and WM266-4), gliomas (T98G and MO59K), bladder (RT-4 and UM-UC-3), colon (Caco-2), lung (H1650), pancreatic (PANC-1), and breast (MCF-7 and MDA:MB-231); (2) inhibition of PKCvarepsilon expression using specific siRNA inhibits Stat3Ser727 phosphorylation, Stat3-DNA binding, Stat3-regulated gene expression as well as cell invasion; and (3) PKCvarepsilon mediates Stat3Ser727 phosphorylation through integration with the MAPK cascade (RAF-1, MEK1/2, and ERK1/2). The results indicate that PKCvarepsilon-mediated Stat3Ser727 phosphorylation is essential for constitutive activation of Stat3 and cell invasion in various human cancers.

MeSH Terms
Brain Neoplasms/enzymology,genetics Carcinoma, Squamous Cell/enzymology,genetics Cell Line, Tumor Conserved Sequence Gene Expression Regulation, Enzymologic Glioma/enzymology,genetics Humans Male Mitogen-Activated Protein Kinase 3/metabolism Mitogen-Activated Protein Kinase Kinases/metabolism Nuclear Matrix-Associated Proteins/metabolism Nucleocytoplasmic Transport Proteins/metabolism Oncogenes Phosphorylation Prostatic Neoplasms/enzymology,genetics Protein Kinase C-epsilon/genetics,metabolism STAT3 Transcription Factor/chemistry,genetics,metabolism
Chemicals
Nuclear Matrix-Associated Proteins Nucleocytoplasmic Transport Proteins RAE1 protein, human STAT3 Transcription Factor STAT3 protein, human Protein Kinase C-epsilon Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinase Kinases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Aziz M H
Department of Human Oncology, Wisconsin Institutes for Medical Research, Paul P. Carbone Comprehensive Cancer, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53792, USA.
Hafeez B B
Sand J M
Pierce D B
Aziz S W
Dreckschmidt N E
Verma A K
References (43)
43 references, click to expand
  1. Transgenic mice overexpressing protein kinase C epsilon in their epidermis exhibit reduced papilloma burden but enhanced carcinoma formation after tumor promotion.
    Cancer Res. 2000 Feb 1;60(3):595-602 PMID: 10676642
  2. Cancer statistics, 2009.
    CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49 PMID: 19474385
  3. Roles of STAT3 defined by tissue-specific gene targeting.
    Oncogene. 2000 May 15;19(21):2607-11 PMID: 10851059
  4. Serine phosphorylation of STATs.
    Oncogene. 2000 May 15;19(21):2628-37 PMID: 10851062
  5. Protein kinase C-epsilon transgenic mice: a unique model for metastatic squamous cell carcinoma.
    Cancer Res. 2001 Feb 1;61(3):808-12 PMID: 11221859
  6. MSK1 and JNKs mediate phosphorylation of STAT3 in UVA-irradiated mouse epidermal JB6 cells.
    J Biol Chem. 2001 Nov 9;276(45):42534-42 PMID: 11553624
  7. Protein kinase C: structural and spatial regulation by phosphorylation, cofactors, and macromolecular interactions.
    Chem Rev. 2001 Aug;101(8):2353-64 PMID: 11749377
  8. Protein kinase cepsilon has the potential to advance the recurrence of human prostate cancer.
    Cancer Res. 2002 Apr 15;62(8):2423-9 PMID: 11956106
  9. Ataxia telangiectasia mutated proteins, MAPKs, and RSK2 are involved in the phosphorylation of STAT3.
    J Biol Chem. 2003 Apr 11;278(15):12650-9 PMID: 12562765
  10. Protein kinase Cepsilon is linked to 12-O-tetradecanoylphorbol-13-acetate-induced tumor necrosis factor-alpha ectodomain shedding and the development of metastatic squamous cell carcinoma in protein kinase Cepsilon transgenic mice.
    Cancer Res. 2003 Oct 1;63(19):6547-55 PMID: 14559850
  11. A STAT3 dimer formed by inter-chain disulphide bridging during oxidative stress.
    Biochem Biophys Res Commun. 2004 Sep 24;322(3):1005-11 PMID: 15336564
  12. Disruption of Stat3 reveals a critical role in both the initiation and the promotion stages of epithelial carcinogenesis.
    J Clin Invest. 2004 Sep;114(5):720-8 PMID: 15343391
  13. Getting the message across, STAT! Design principles of a molecular signaling circuit.
    J Cell Biol. 2004 Oct 25;167(2):197-201 PMID: 15504906
  14. Modulating protein kinase C signal transduction.
    Adv Pharmacol. 1998;44:91-145 PMID: 9547885
  15. The extended protein kinase C superfamily.
    Biochem J. 1998 Jun 1;332 ( Pt 2):281-92 PMID: 9601053
  16. Protein kinase C isoenzyme patterns characteristically modulated in early prostate cancer.
    Am J Pathol. 1999 Jan;154(1):137-44 PMID: 9916928
  17. Protein kinase C delta associates with and phosphorylates Stat3 in an interleukin-6-dependent manner.
    J Biol Chem. 1999 Aug 20;274(34):24392-400 PMID: 10446219
  18. Protein kinase C epsilon is an endogenous photosensitizer that enhances ultraviolet radiation-induced cutaneous damage and development of squamous cell carcinomas.
    Cancer Res. 2004 Nov 1;64(21):7756-65 PMID: 15520180
  19. Integrin signaling links protein kinase Cepsilon to the protein kinase B/Akt survival pathway in recurrent prostate cancer cells.
    Oncogene. 2004 Nov 11;23(53):8659-72 PMID: 15467757
  20. Targeting the STAT pathway in head and neck cancer: recent advances and future prospects.
    Curr Cancer Drug Targets. 2004 Dec;4(8):637-51 PMID: 15578920
  21. Implication of STAT3 signaling in human colonic cancer cells during intestinal trefoil factor 3 (TFF3) -- and vascular endothelial growth factor-mediated cellular invasion and tumor growth.
    Cancer Res. 2005 Jan 1;65(1):195-202 PMID: 15665295
  22. The signal transduction networks required for phosphorylation of STAT1 at Ser727 in mouse epidermal JB6 cells in the UVB response and inhibitory mechanisms of tea polyphenols.
    Carcinogenesis. 2005 Feb;26(2):331-42 PMID: 15550455
  23. Protein kinase C epsilon signals ultraviolet light-induced cutaneous damage and development of squamous cell carcinoma possibly through Induction of specific cytokines in a paracrine mechanism.
    Photochem Photobiol. 2005 Jan-Feb;81(1):9-18 PMID: 15458367
  24. Identification of a genetic signature of activated signal transducer and activator of transcription 3 in human tumors.
    Cancer Res. 2005 Jun 15;65(12):5054-62 PMID: 15958548
  25. Targeting STAT3 affects melanoma on multiple fronts.
    Cancer Metastasis Rev. 2005 Jun;24(2):315-27 PMID: 15986140
  26. Protein kinase C-epsilon regulates the apoptosis and survival of glioma cells.
    Cancer Res. 2005 Aug 15;65(16):7301-9 PMID: 16103081
  27. Protein kinase C epsilon is a predictive biomarker of aggressive breast cancer and a validated target for RNA interference anticancer therapy.
    Cancer Res. 2005 Sep 15;65(18):8366-71 PMID: 16166314
  28. Role of the protein kinase C-epsilon-Raf-1-MEK-1/2-p44/42 MAPK signaling cascade in the activation of signal transducers and activators of transcription 1 and 3 and induction of cyclooxygenase-2 after ischemic preconditioning.
    Circulation. 2005 Sep 27;112(13):1971-8 PMID: 16172266
  29. Opposing actions of STAT-1 and STAT-3.
    Growth Factors. 2005 Sep;23(3):177-82 PMID: 16243709
  30. The role of IL-6 and STAT3 in inflammation and cancer.
    Eur J Cancer. 2005 Nov;41(16):2502-12 PMID: 16199153
  31. A novel RING-type ubiquitin ligase breast cancer-associated gene 2 correlates with outcome in invasive breast cancer.
    Cancer Res. 2005 Nov 15;65(22):10401-12 PMID: 16288031
  32. Links between alpha-catenin, NF-kappaB, and squamous cell carcinoma in skin.
    Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2322-7 PMID: 16452166
  33. Signal transducers and activators of transcription (STATs): Novel targets of chemopreventive and chemotherapeutic drugs.
    Curr Cancer Drug Targets. 2006 Mar;6(2):107-21 PMID: 16529541
  34. Novel RING E3 ubiquitin ligases in breast cancer.
    Neoplasia. 2006 Aug;8(8):689-95 PMID: 16925951
  35. Targeted disruption of protein kinase C epsilon reduces cell invasion and motility through inactivation of RhoA and RhoC GTPases in head and neck squamous cell carcinoma.
    Cancer Res. 2006 Oct 1;66(19):9379-84 PMID: 17018591
  36. Protein kinase C epsilon, which sensitizes skin to sun's UV radiation-induced cutaneous damage and development of squamous cell carcinomas, associates with Stat3.
    Cancer Res. 2007 Feb 1;67(3):1385-94 PMID: 17283176
  37. Protein kinase C and other diacylglycerol effectors in cancer.
    Nat Rev Cancer. 2007 Apr;7(4):281-94 PMID: 17384583
  38. Protein kinase Cepsilon makes the life and death decision.
    Cell Signal. 2007 Aug;19(8):1633-42 PMID: 17537614
  39. Protein kinase C epsilon is overexpressed in primary human non-small cell lung cancers and functionally required for proliferation of non-small cell lung cancer cells in a p21/Cip1-dependent manner.
    Cancer Res. 2007 Jul 1;67(13):6053-63 PMID: 17616661
  40. Protein kinase Cepsilon interacts with Stat3 and regulates its activation that is essential for the development of skin cancer.
    Mol Carcinog. 2007 Aug;46(8):646-53 PMID: 17583567
  41. Protein kinase Cepsilon interacts with signal transducers and activators of transcription 3 (Stat3), phosphorylates Stat3Ser727, and regulates its constitutive activation in prostate cancer.
    Cancer Res. 2007 Sep 15;67(18):8828-38 PMID: 17875724
  42. Amplitude control of protein kinase C by RINCK, a novel E3 ubiquitin ligase.
    J Biol Chem. 2007 Nov 16;282(46):33776-87 PMID: 17893151
  43. Eyes wide shut: protein kinase C isozymes are not the only receptors for the phorbol ester tumor promoters.
    Mol Carcinog. 2000 May;28(1):5-11 PMID: 10820483
Article Info
Journal
Oncogene
Abbr.
Oncogene
ISSN
1476-5594
DOI
10.1038/onc.2010.63
Published
2010-05-27
Epub
2010-00-15
Pages
3100-9
Language
English
Region
England
NLM ID
8711562
PMCID
PMC2947343
Subset
IM
Grants
NCI NIH HHS · R01 CA035368 · United States
NCI NIH HHS · R01 CA035368-22A1 · United States
NCI NIH HHS · CA35368 · United States
External Links
PubMed source DOI: 10.1038/onc.2010.63 PMC Full Text View journal details
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