On the mechanisms of 12-otetradecanoylphorbol-13-acetate-induced growth arrest in pancreatic cancer cells

Mohammad R. Salabat, Xian Z. Ding, Jan B. Flesche, Micheal B. Ujiki, Tyler P. Robin, Mark S. Talamonti, Richard H. Bell, Thomas E. Adrian

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

OBJECTIVES: Protein kinase C (PKC) is involved in cell growth, differentiation, and apoptosis. We investigated the effects of the PKC activator, the tetradecanylphorbol acetate (TPA), in human pancreatic cancer cells. METHODS: Cell proliferation was measured by thymidine incorporation. Expression of cell cycle proteins was investigated by Western blot. Real-time reverse transcriptase-polymerase chain reaction was used to measure p21 WAF1 messenger RNA expression, whereas knockdown of its expression was accomplished with a specific small interferring RNA. Cell cycle phases were determined by flow cytometry. RESULTS: TPA time and concentration dependently inhibited thymidine incorporation in Panc-1 and CD18 cells and induced G2/M cell cycle arrest. The TPA decreased cyclin A and B expression, increased cyclin E, and markedly increased the expression of p21WAF1 at both the messenger RNA and protein levels. TPA-induced p21WAF1 expression and growth inhibition were blocked by the PKC inhibitor, bisindoylmaleimide. TPA induced extracellular signal-regulated kinase1/2 phosphorylation, whereas the MEK inhibitor, PD98059, blocked the TPA-induced p21WAF1 expression. Small interferring RNA targeted to p21WAF1 blocked TPA-induced p21WAF1 protein expression but not TPA-induced cell growth arrest. CONCLUSIONS: TPA-induced p21WAF1 expression is mediated by the MEK/ERK pathway but is not involved in TPA-induced growth inhibition. In contrast, cyclin A and cyclin B are likely involved in TPA-induced G2/M arrest because both proteins are involved in S phase and G2/M transition during cell proliferation.

Original languageEnglish
Pages (from-to)148-155
Number of pages8
JournalPancreas
Volume33
Issue number2
DOIs
Publication statusPublished - Aug 2006
Externally publishedYes

Keywords

  • Cyclin A
  • Cyclin B
  • G2/M phase arrest
  • Pancreatic cancer
  • Protein kinase C
  • TPA
  • Tumor-promoting phorbol ester
  • p21

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Hepatology
  • Endocrinology

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