Abstract
The mitogen-activated protein kinase (MAPK) pathway is constitutively activated in the majority of melanomas, promoting cell survival, proliferation and migration. In addition, anti-apoptotic Bcl-2 family proteins Mcl-1, Bcl-xL and Bcl-2 are frequently overexpressed, contributing to melanoma's well-documented chemoresistance. Recently, it was reported that the combination of MAPK pathway inhibition by specific MEK inhibitors and Bcl-2 family inhibition by BH3-mimetic ABT-737 synergistically induces apoptotic cell death in melanoma cell lines. Here we provide the first evidence that inhibition of another key MAPK, p38, synergistically induces apoptosis in melanoma cells in combination with ABT-737. We also provide novel mechanistic data demonstrating that inhibition of p38 increases expression of pro-apoptotic Bcl-2 protein PUMA. Furthermore, we demonstrate that PUMA can be cleaved by a caspase-dependent mechanism during apoptosis and identify what appears to be the PUMA cleavage product. Thus, our findings suggest that the combination of ABT-737 and inhibition of p38 is a promising, new treatment strategy that acts through a novel PUMA-dependent mechanism.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis Regulatory Proteins / metabolism*
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Biphenyl Compounds / pharmacology*
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Caspases / metabolism
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Cell Death / drug effects
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Cell Line, Tumor
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Cell Survival / drug effects
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Drug Synergism
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Enzyme Activation / drug effects
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Gene Knockdown Techniques
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Humans
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Imidazoles / pharmacology
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Melanoma / enzymology
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Melanoma / pathology*
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Myeloid Cell Leukemia Sequence 1 Protein
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Nitrophenols / pharmacology*
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Piperazines / pharmacology
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Pyridines / pharmacology
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Skin Neoplasms / enzymology
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Skin Neoplasms / pathology*
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Sulfonamides / pharmacology*
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Up-Regulation / drug effects
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
Substances
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ABT-737
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Apoptosis Regulatory Proteins
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BBC3 protein, human
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Biphenyl Compounds
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Imidazoles
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Myeloid Cell Leukemia Sequence 1 Protein
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Nitrophenols
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Piperazines
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Pyridines
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Sulfonamides
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p38 Mitogen-Activated Protein Kinases
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Caspases
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4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole