MEK Inhibition of Pancreatic Carcinoma Cells by U0126 and Its Effect in Combination with Sulindac

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Objectives: The MAP kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) pathway is critical for cell growth and survival. In the current study, we examined the effect of inhibiting the MEK-ERK pathway in pancreatic tumor cells with the MEK-specific inhibitor U0126. In addition, we investigated whether the MEK-ERK pathway influenced the response of pancreatic cancer cells to nonsteroidal antiinflammatory drugs (NSAIDs). Methods: Cell growth was monitored by a colorimetric proliferation assay and cell counts. Cell cycle analysis was performed using flow cytometry. Apoptosis was measured using a DNA fragmentation ELISA. Protein expression was detected by Western blot. Conclusion: Treatment with U0126 dose dependently inhibited the growth of 3 human pancreatic carcinoma cell lines (BxPC-3, PANC-1, and MIA PaCa-2). U0126 treatment resulted in cell-cycle alterations but did not induce apoptosis. Growth inhibitory concentrations of NSAIDs unexpectedly increased ERK phosphorylation in BxPC-3 and MIA PaCa-2 cells. We therefore evaluated the effect of treating pancreatic tumor cells with the combination of the NSAID sulindac and U0126. Treatment with U0126 complemented sulindac-induced growth inhibition in BxPC-3 and PANC-1 cells. The expression of several cell cycle (p21, p27, cyclin D1) and apoptotic (survivin, Bcl-xL) regulatory proteins was altered after U0126 and/or sulindac treatment. Our findings suggest that inhibition of the MEK-ERK signaling pathway may sensitize pancreatic tumor cells to NSAID therapy.

Original languageEnglish
Pages (from-to)337-344
Number of pages8
JournalPancreas
Volume27
Issue number4
DOIs
StatePublished - Nov 2003

Fingerprint

Sulindac
Mitogen-Activated Protein Kinase Kinases
Extracellular Signal-Regulated MAP Kinases
Anti-Inflammatory Agents
Growth
Cell Cycle
Pharmaceutical Preparations
Apoptosis
Neoplasms
Critical Pathways
Cyclin D1
DNA Fragmentation
Therapeutics
U 0126
Pancreatic Carcinoma
Pancreatic Neoplasms
Cell Survival
Flow Cytometry
Proteins
Cell Count

Keywords

  • Extracellular signal-regulated kinase
  • Nonsteroidal anti-inflammatory drugs
  • Pancreatic cancer
  • Sulindac
  • U0126

ASJC Scopus subject areas

  • Gastroenterology
  • Endocrinology

Cite this

MEK Inhibition of Pancreatic Carcinoma Cells by U0126 and Its Effect in Combination with Sulindac. / Yip-Schneider, Michele; Schmidt, C.

In: Pancreas, Vol. 27, No. 4, 11.2003, p. 337-344.

Research output: Contribution to journalArticle

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