Protein kinase cβ is an effective target for chemoprevention of colon cancer

Alan P Fields, Shelly R. Calcagno, Murli Krishna, Sofija Rak, Michael Leitges, Nicole R Murray

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Colon cancer develops over a period of 10 to 15 years, providing a window of opportunity for chemoprevention and early intervention. However, few molecular targets for effective colon cancer chemoprevention have been characterized and validated. Protein kinase CβII (PKCβII) plays a requisite role in the initiation of colon carcinogenesis in a preclinical mouse model by promoting proliferation and increased β-catenin accumulation. In this study, we test the hypothesis that PKCβII is an effective target for colon cancer chemoprevention using enzastaurin (LY317615), a PKCβ-selective inhibitor, in a mouse model of colon car-cinogenesis. We find that enzastaurin potently reduces azoxymethane-induced colon tumor initiation and progression by inhibiting PKCβII-mediated tumor cell proliferation and β-catenin accumulation. Biochemically, enzastaurin reduces expression of the PKCβII- and β-catenin/T-cell factor-regulated genes PKCβII, cyclooxygenase II,and vascular endothelial growth factor, three genes implicated in colon carcinogenesis. Our results show that enzastaurin is an effective chemopreventive agent in a mouse model of sporadic colon cancer that significantly reduces both tumor initiation and progression by inhibiting expression of proproliferative genes. Thus, PKCβII is an important target for colon cancer chemoprevention and the PKCβ-selective inhibitor enzastaurin may represent an effective chemo-preventive agent in patients at high riskfor colon cancer.

Original languageEnglish (US)
Pages (from-to)1643-1650
Number of pages8
JournalCancer Research
Volume69
Issue number4
DOIs
StatePublished - Feb 15 2009

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Chemoprevention
Colonic Neoplasms
Protein Kinases
Catenins
Colon
Carcinogenesis
Azoxymethane
TCF Transcription Factors
Neoplasms
Proxy
Prostaglandin-Endoperoxide Synthases
Vascular Endothelial Growth Factor A
Cell Proliferation
enzastaurin
Gene Expression
Genes
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Protein kinase cβ is an effective target for chemoprevention of colon cancer. / Fields, Alan P; Calcagno, Shelly R.; Krishna, Murli; Rak, Sofija; Leitges, Michael; Murray, Nicole R.

In: Cancer Research, Vol. 69, No. 4, 15.02.2009, p. 1643-1650.

Research output: Contribution to journalArticle

Fields, Alan P ; Calcagno, Shelly R. ; Krishna, Murli ; Rak, Sofija ; Leitges, Michael ; Murray, Nicole R. / Protein kinase cβ is an effective target for chemoprevention of colon cancer. In: Cancer Research. 2009 ; Vol. 69, No. 4. pp. 1643-1650.
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