Abstract
In the present study we have explored the sensitivity of ovarian cancer cells to TRAIL and proteasome inhibitors. Particularly, we have explored the capacity of proteasome inhibitors to bypass TRAIL resistance of ovarian cancer cells. For these studies we have used the A2780 ovarian cancer cell line and its chemoresistant derivatives A2780/DDP and A2780/ADR, providing evidence that: (i) the three cell lines are either scarcely sensitive (A2780 and A2780/ADR) or moderately sensitive (A2780/DDP) to the cytotoxic effects of TRAIL; (ii) the elevated c-FLIP expression observed in ovarian cancer cells is a major determinant of TRAIL resistance of these cells; (iii) proteasome inhibitors (PS-341 or MG132) are able to exert a significant pro-apoptotic effect and to greatly enhance the sensitivity of both chemosensitive and chemoresistant A2780 cells to TRAIL; (iv) proteasome inhibitors damage mitochondria through stabilization of BH3-only proteins, Bax and caspase activation and significantly enhance TRAIL-R2 expression; (v) TRAIL-R2, but not TRAIL-R1, mediates the apoptotic effects of TRAIL on ovarian cancer cells. Importantly, studies on primary ovarian cancer cells have shown that these cells are completely resistant to TRAIL and proteasome inhibitors markedly enhance the sensitivity of these cells to TRAIL. Given the high susceptibility of ovarian cancer cells to proteasome inhibitors, our results further support the experimental use of these compounds in the treatment of ovarian cancer.
MeSH terms
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Antibodies, Monoclonal / metabolism
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Antibodies, Monoclonal / pharmacology
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Apoptosis / drug effects
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Bcl-2-Like Protein 11
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Boronic Acids / pharmacology
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Boronic Acids / therapeutic use
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Bortezomib
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CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
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CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
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Caspases / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Enzyme Activation
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Female
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Humans
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Leupeptins / pharmacology
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Leupeptins / therapeutic use
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mitochondria / metabolism
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Ovarian Neoplasms / drug therapy*
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Ovarian Neoplasms / metabolism*
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Ovarian Neoplasms / pathology
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Protease Inhibitors* / metabolism
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Protease Inhibitors* / pharmacology
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Protease Inhibitors* / therapeutic use
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Proteasome Endopeptidase Complex* / metabolism
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Proteasome Inhibitors
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Pyrazines / pharmacology
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Pyrazines / therapeutic use
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RNA, Small Interfering / metabolism
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Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
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TNF-Related Apoptosis-Inducing Ligand / metabolism*
Substances
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Boronic Acids
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Leupeptins
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Membrane Proteins
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Protease Inhibitors
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Proteasome Inhibitors
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Pyrazines
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RNA, Small Interfering
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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TNF-Related Apoptosis-Inducing Ligand
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Bortezomib
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lexatumumab
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Caspases
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Proteasome Endopeptidase Complex
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde
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mapatumumab