Abstract
Defective apoptosis not only promotes tumorigenesis, but also can confound chemotherapeutic response. Here we demonstrate that the proapoptotic BH3-only protein BIM is a tumor suppressor in epithelial solid tumors and also is a determinant in paclitaxel sensitivity in vivo. Furthermore, the H-ras/mitogen-activated protein kinase (MAPK) pathway conferred resistance to paclitaxel that was dependent on functional inactivation of BIM. Whereas paclitaxel induced BIM accumulation and BIM-dependent apoptosis in vitro and in tumors in vivo, the H-ras/MAPK pathway suppressed this BIM induction by phosphorylating BIM and targeting BIM for degradation in proteasomes. The proteasome inhibitor Velcade (P-341, Bortezomib) restored BIM induction, abrogated H-ras-dependent paclitaxel resistance, and promoted BIM-dependent tumor regression, suggesting the potential benefits of combinatorial chemotherapy of Velcade and paclitaxel.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antineoplastic Agents, Phytogenic / metabolism
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Antineoplastic Agents, Phytogenic / therapeutic use*
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins
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Bcl-2-Like Protein 11
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Boronic Acids / therapeutic use
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Bortezomib
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Line
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Drug Resistance, Neoplasm
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Drug Therapy, Combination
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Gene Expression Regulation
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Genes, ras
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Humans
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MAP Kinase Signaling System / physiology
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Mice, Knockout
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Neoplasms, Glandular and Epithelial / drug therapy*
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Neoplasms, Glandular and Epithelial / metabolism*
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Paclitaxel / metabolism
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Paclitaxel / therapeutic use*
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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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Pyrazines / therapeutic use
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Tumor Suppressor Protein p53 / metabolism
Substances
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Antineoplastic Agents, Phytogenic
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Apoptosis Regulatory Proteins
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BBC3 protein, human
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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Boronic Acids
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Carrier Proteins
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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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Pyrazines
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Tumor Suppressor Protein p53
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Bortezomib
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Proteasome Endopeptidase Complex
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Paclitaxel