Taxol-induced apoptosis depends on MAP kinase pathways (ERK and p38) and is independent of p53

Oncogene. 2001 Jan 11;20(2):147-55. doi: 10.1038/sj.onc.1204062.

Abstract

The anti-cancer agent paclitaxel (Taxol) stabilizes microtubules leading to G2/M cell cycle arrest and apoptotic cell death. In order to analyse the molecular mechanisms of Taxol-induced cytotoxicity, we studied the involvement of mitogen-activated protein kinases (MAPK) ERK and p38 as well as the p53 pathways in Taxol-induced apoptosis. The human breast carcinoma cell line MCF7 and its derivatives, MCF7/HER-2 and MDD2, were used in the study. We found that Taxol treatment strongly activated ERK, p38 MAP kinase and p53 in MAP kinase MCF7 cells prior to apoptosis. PD98059 or SB203580, specific inhibitors of ERK and p38 kinase activities, significantly decreased apoptosis, leaving the surviving cells arrested in G2/M. These inhibitors did not significantly affect Taxol-induced alterations in the cell cycle regulatory proteins Rb, p53, p21/Waf1 and Cdk-2. In addition, inactivation of p53 did not affect cellular sensitivity to Taxol killing. However, cells with inactivated p53, unlike cells harboring wild type p53, failed to arrest in G2/M after treatment with Taxol and continued to divide or go into apoptosis. Our data show that both ERK and p38 MAP kinase cascades are essential for apoptotic response to Taxol-induced cellular killing and are independent of p53 activity. However, p53 may serve as a survival factor in breast carcinoma cells treated with Taxol by blocking cells in G2/M phase of the cell cycle.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • CDC2-CDC28 Kinases*
  • Carcinoma / drug therapy
  • Carcinoma / metabolism
  • Carcinoma / pathology
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin-Dependent Kinases / drug effects
  • Cyclin-Dependent Kinases / metabolism
  • Cyclins / drug effects
  • Cyclins / metabolism
  • Enzyme Inhibitors / pharmacology
  • Female
  • Flavonoids / pharmacology
  • G2 Phase / drug effects
  • Humans
  • Imidazoles / pharmacology
  • MAP Kinase Kinase Kinase 1*
  • MAP Kinase Signaling System / drug effects*
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / drug effects
  • Mitogen-Activated Protein Kinases / metabolism
  • Mitosis / drug effects
  • Paclitaxel / pharmacology*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / drug effects
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Pyridines / pharmacology
  • Rats
  • Receptor, ErbB-2 / drug effects
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism
  • Retinoblastoma Protein / drug effects
  • Retinoblastoma Protein / metabolism
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / drug effects
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Antineoplastic Agents, Phytogenic
  • CDKN1A protein, human
  • Cdkn1a protein, rat
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Enzyme Inhibitors
  • Flavonoids
  • Imidazoles
  • Pyridines
  • Retinoblastoma Protein
  • Tumor Suppressor Protein p53
  • Receptor, ErbB-2
  • Protein-Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • Cdk2 protein, rat
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 1
  • MAP3K1 protein, human
  • SB 203580
  • Paclitaxel
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one