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

Oncogene
S S BacusR Seger

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 kil...Continue Reading

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Citations

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