Overexpression of ErbB2 blocks Taxol-induced apoptosis by upregulation of p21Cip1, which inhibits p34Cdc2 kinase

Mol Cell. 1998 Nov;2(5):581-91. doi: 10.1016/s1097-2765(00)80157-4.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • CDC2 Protein Kinase / antagonists & inhibitors
  • CDC2 Protein Kinase / genetics
  • CDC2 Protein Kinase / metabolism*
  • CDC2-CDC28 Kinases*
  • Cell Line
  • Cyclin B / metabolism
  • Cyclin B1
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin-Dependent Kinases / genetics
  • Cyclin-Dependent Kinases / metabolism
  • Cyclins / genetics
  • Cyclins / metabolism*
  • DNA Fragmentation
  • Fibroblasts
  • Flow Cytometry
  • Humans
  • Kinetin
  • Mice
  • Oligonucleotides, Antisense / genetics
  • Paclitaxel / pharmacology*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Purines / pharmacology
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism*
  • Transfection
  • Tumor Cells, Cultured
  • Up-Regulation / genetics*

Substances

  • CCNB1 protein, human
  • CDKN1A protein, human
  • Ccnb1 protein, mouse
  • Cdkn1a protein, mouse
  • Cyclin B
  • Cyclin B1
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Oligonucleotides, Antisense
  • Purines
  • olomoucine
  • Receptor, ErbB-2
  • Protein-Serine-Threonine Kinases
  • CDC2 Protein Kinase
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • Cdk2 protein, mouse
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases
  • Kinetin
  • Paclitaxel