Abstract
Overexpression of the receptor tyrosine kinase p185ErbB2 confers Taxol resistance in breast cancers. Here, we investigated the underlying mechanisms and found that overexpression of p185ErbB2 inhibits Taxol-induced apoptosis. Taxol activates p34Cdc2 kinase in MDA-MB-435 breast cancer cells, leading to cell cycle arrest at the G2/M phase and, subsequently, apoptosis. A chemical inhibitor of p34Cdc2 and a dominant-negative mutant of p34Cdc2 blocked Taxol-induced apoptosis in these cells. Overexpression of p185ErbB2 in MDA-MB-435 cells by transfection transcriptionally upregulates p21Cip1, which associates with p34Cdc2, inhibits Taxol-mediated p34Cdc2 activation, delays cell entrance to G2/M phase, and thereby inhibits Taxol-induced apoptosis. In p21Cip1 antisense-transfected MDA-MB-435 cells or in p21-/- MEF cells, p185ErbB2 was unable to inhibit Taxol-induced apoptosis. Therefore, p21Cip1 participates in the regulation of a G2/M checkpoint that contributes to resistance to Taxol-induced apoptosis in p185ErbB2-overexpressing breast cancer cells.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / drug effects*
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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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CDC2 Protein Kinase / antagonists & inhibitors
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CDC2 Protein Kinase / genetics
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CDC2 Protein Kinase / metabolism*
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CDC2-CDC28 Kinases*
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Cell Line
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Cyclin B / metabolism
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Cyclin B1
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclin-Dependent Kinases / genetics
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Cyclin-Dependent Kinases / metabolism
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Cyclins / genetics
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Cyclins / metabolism*
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DNA Fragmentation
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Fibroblasts
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Flow Cytometry
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Humans
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Kinetin
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Mice
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Oligonucleotides, Antisense / genetics
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Paclitaxel / pharmacology*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Purines / pharmacology
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Receptor, ErbB-2 / genetics
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Receptor, ErbB-2 / metabolism*
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Transfection
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Tumor Cells, Cultured
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Up-Regulation / genetics*
Substances
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CCNB1 protein, human
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CDKN1A protein, human
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Ccnb1 protein, mouse
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Cdkn1a protein, mouse
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Cyclin B
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Cyclin B1
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Oligonucleotides, Antisense
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Purines
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olomoucine
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Receptor, ErbB-2
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Protein Serine-Threonine Kinases
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CDC2 Protein Kinase
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CDC2-CDC28 Kinases
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CDK2 protein, human
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Cdk2 protein, mouse
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinases
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Kinetin
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Paclitaxel