Inhibition of extracellular-signal regulated kinases 1/2 is required for apoptosis of human colon cancer cells in vitro by sulindac metabolites.

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Rice PL, Beard KS, Driggers LJ, Ahnen DJ

Inhibition of extracellular-signal regulated kinases 1/2 is required for apoptosis of human colon cancer cells in vitro by sulindac metabolites.

Cancer Res. 2004 Nov 15;64(22):8148-51.

PubMed ID

15548677 [ View in PubMed

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Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) including sulindac have shown potent chemopreventive and tumor regressive effects against colorectal cancer, the second leading cause of cancer death in the United States. However, the mechanisms by which sulindac inhibits tumor cell growth are not completely understood. We previously reported that sulindac metabolites inhibit the mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signaling cascade in colorectal cancer cell lines at doses that induce apoptosis, and inhibition of MEK/ERK activity with U0126 is sufficient to induce apoptotic cell death. To determine whether inhibition of MEK/ERK activity is necessary for sulindac-induced apoptosis of human colon cancer cells, stable transfectants were created that express an activated MEK1 gene in HT29 cells. HT29-MEK1(R4F) clones displayed a 10- to 20-fold increase in MEK1 activity compared with control HT29-pCEP4 clones. When compared with control HT29-pCEP4 clones, HT29-MEK1(R4F) clones were resistant to both apoptosis and inhibition of ERK1/2 phosphorylation induced by sulindac metabolites. These results suggest that inhibition of MEK/ERK signaling is necessary for the induction of apoptosis by sulindac metabolites.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Sulindac	Mitogen-activated protein kinase 3	Protein	Humans	Unknown	Inhibitor	Details