Sulindac sulfide inhibits epidermal growth factor-induced phosphorylation of extracellular-regulated kinase 1/2 and Bad in human colon cancer cells.
Colorectal cancer is the second leading cause of cancer death in the United States. Nonsteroidal anti-inflammatory drugs including sulindac are promising chemopreventive agents for colorectal cancer. Sulindac and selective cyclooxygenase (COX)-2 inhibitors cause regression of colonic polyps in familial polyposis patients. Sulindac induces apoptotic cell death in cancer cells in ... vitro and in vivo. In tumor cells, activation of extracellular-regulated kinase (ERK) 1/2 results in phosphorylation of several ERK1/2 effectors, including the proapoptotic protein Bad. Phosphorylation of Ser112 by ERK1/2 inactivates Bad and protects the tumor cell from apoptosis. Sulindac metabolites and other nonsteroidal anti-inflammatory drugs selectively inhibit ERK1/2 phosphorylation in human colon cancer cells. In this study we show that epidermal growth factor (EGF) strongly induces phosphorylation of ERK1/2 and Bad in HT29 colon cancer cells. EGF-stimulated phosphorylation of ERK and Bad is blocked by pretreatment with U0126, a selective MAP kinase kinase (MKK)1/2 inhibitor. Similarly, pretreatment with sulindac sulfide blocks the ability of EGF to induce ERK1/2 and Bad phosphorylation, but also down-regulates total Bad but not ERK1/2 protein levels. The ability of sulindac to block ERK1/2 signaling by the EGF receptor may account for at least part of its potent growth-inhibitory effects against cancer cells.
Mesh Terms:
Antineoplastic Agents, Butadienes, Carrier Proteins, Caspase Inhibitors, Caspases, Colonic Neoplasms, Enzyme Activation, Epidermal Growth Factor, Humans, MAP Kinase Kinase 1, MAP Kinase Kinase 2, MAP Kinase Signaling System, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinase Kinases, Mitogen-Activated Protein Kinases, Nitriles, Phosphorylation, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Sulindac, Tumor Cells, Cultured, bcl-Associated Death Protein
Antineoplastic Agents, Butadienes, Carrier Proteins, Caspase Inhibitors, Caspases, Colonic Neoplasms, Enzyme Activation, Epidermal Growth Factor, Humans, MAP Kinase Kinase 1, MAP Kinase Kinase 2, MAP Kinase Signaling System, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinase Kinases, Mitogen-Activated Protein Kinases, Nitriles, Phosphorylation, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Sulindac, Tumor Cells, Cultured, bcl-Associated Death Protein
Cancer Res.
Date: Feb. 01, 2003
PubMed ID: 12566304
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