Overexpression of ErbB2 blocks Taxol-induced apoptosis by upregulation of p21Cip1, which inhibits p34Cdc2 kinase.
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.
Yu
D
D
Department of Surgical Oncology, University of Texas, M. D. Anderson Cancer Center, Houston 77030, USA.
Jing
T
T
Liu
B
B
Yao
J
J
Tan
M
M
McDonnell
T J
TJ
Hung
M C
MC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D042846:CDC2-CDC28 Kinases; D002460:Cell Line; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D053938:DNA Fragmentation; D005347:Fibroblasts; D005434:Flow Cytometry; D006801:Humans; D007701:Kinetin; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000235:genetics; D017239:Paclitaxel / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000235:genetics*
D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; D019926:Cyclin B; D056744:Cyclin B1; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases; D016213:Cyclins; D007701:Kinetin; D016376:Oligonucleotides, Antisense; D017239:Paclitaxel; D017346:Protein Serine-Threonine Kinases; D011687:Purines; D018719:Erb-b2 Receptor Tyrosine Kinases; C534699:CCNB1 protein, human; C493956:CDKN1A protein, human; C534700:Ccnb1 protein, mouse; C493957:Cdkn1a protein, mouse; C090046:olomoucine; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse