Abstract
Bc1-2 protein is a potent anti-apoptotic protein that inhibits a mitochondria-operated pathway of apoptosis in many cells. DNA damaging agents and death receptor ligands can activate this mitochondrial apoptotic mechanism. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been suggested to escape from the inhibitory action of Bc1-2 protein. We show that in human breast tumor MCF-7 cells, TRAIL induced a mitochondrial pathway of apoptosis that involved cytochrome c release from mitochondria and activation of caspase 9. The DNA damaging drug doxorubicin also activated this mitochondria-regulated mechanism of apoptosis, which was inhibited in Bc1-2-overexpressing cells. We also demonstrate that in MCF-7 cells Bc1-2 might confer resistance to TRAIL-induced apoptosis, depending on the expression levels of the anti-apoptotic protein. These results indicate that enhanced expression of Bc1-2 in tumor cells can render these cells less sensitive not only to chemotherapeutic drugs but also to TRAIL.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / genetics
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology*
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Antibiotics, Antineoplastic / pharmacology*
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects*
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Apoptosis Regulatory Proteins
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology*
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Caspase 9
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Caspases / metabolism
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Cytochrome c Group / metabolism
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DNA Damage
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DNA, Neoplasm / drug effects
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DNA, Neoplasm / genetics
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Doxorubicin / pharmacology*
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Drug Resistance, Neoplasm / physiology*
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Enzyme Activation / drug effects
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Female
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Humans
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Membrane Glycoproteins / pharmacology*
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Mitochondria / drug effects
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Neoplasm Proteins / analysis
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Neoplasm Proteins / physiology*
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Protein Transport / drug effects
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / physiology*
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TNF-Related Apoptosis-Inducing Ligand
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Tubulin / analysis
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / pathology
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Tumor Necrosis Factor-alpha / pharmacology*
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bcl-2-Associated X Protein
Substances
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Antibiotics, Antineoplastic
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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Cytochrome c Group
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DNA, Neoplasm
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Membrane Glycoproteins
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Neoplasm Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Tubulin
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Tumor Necrosis Factor-alpha
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bcl-2-Associated X Protein
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Doxorubicin
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CASP9 protein, human
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Caspase 9
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Caspases