Overexpression of ErbB2 Blocks Taxol-Induced Apoptosis by Upregulation of p21 Cip1, which Inhibits p34 Cdc2 Kinase

Abstract

Overexpression of the receptor tyrosine kinase p185 ErbB2 confers Taxol resistance in breast cancers. Here, we investigated the underlying mechanisms and found that overexpression of p185 ErbB2 inhibits Taxol-induced apoptosis. Taxol activates p34 Cdc2 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 p34 Cdc2 and a dominant-negative mutant of p34 Cdc2 blocked Taxol-induced apoptosis in these cells. Overexpression of p185 ErbB2 in MDA-MB-435 cells by transfection transcriptionally upregulates p21 Cip1, which associates with p34 Cdc2, inhibits Taxol-mediated p34 Cdc2 activation, delays cell entrance to G2/M phase, and thereby inhibits Taxol-induced apoptosis. In p21 Cip1 antisense-transfected MDA-MB-435 cells or in p21 −/− MEF cells, p185 ErbB2 was unable to inhibit Taxol-induced apoptosis. Therefore, p21 Cip1 participates in the regulation of a G2/M checkpoint that contributes to resistance to Taxol-induced apoptosis in p185 ErbB2-overexpressing breast cancer cells.