Abstract
Epithelial cells can be manipulated to undergo apoptosis depending on the balance between pro-survival and apoptotic signals. We showed that TRAIL-induced apoptosis may be differentially regulated by inhibitors of MEK ERK (U0126) or PI3K/Akt (LY294002) pathway in TRAIL-sensitive (HT-29) and TRAIL-resistant (SW620) human epithelial colon cancer cells. U0126 or LY294002 significantly enhanced TRAIL-induced apoptosis in HT-29 cells, but not in SW620 cells. We report a different regulation of the level of an anti-apoptotic Mcl-1 protein under MEK/ERK or PI3K/Akt pathway inhibition and suggest the mechanisms involved. A special attention was paid to the role of the ERK1/2, Akt, and glycogen synthase kinase 3beta.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects*
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Caspase 8 / metabolism
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Cell Survival / drug effects
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Colonic Neoplasms / pathology*
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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HT29 Cells
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Humans
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Keratin-18 / metabolism
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation / drug effects
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Poly(ADP-ribose) Polymerases / metabolism
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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TNF-Related Apoptosis-Inducing Ligand / pharmacology*
Substances
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Enzyme Inhibitors
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Keratin-18
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins c-bcl-2
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TNF-Related Apoptosis-Inducing Ligand
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Poly(ADP-ribose) Polymerases
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Glycogen Synthase Kinase 3
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Mitogen-Activated Protein Kinase Kinases
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Caspase 8