MEK inhibition of pancreatic carcinoma cells by U0126 and its effect in combination with sulindac

Michele T Yip-Schneider, C Max Schmidt
Pancreas 2003, 27 (4): 337-44

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.

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