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Vol. 60, Issue 2, 290-301, August 2001
Department of Molecular Pharmacology, Albert Einstein College of
Medicine, Bronx, New York
Activation of the mitogen-activated protein kinase (MAPK) pathway in
HeLa and Chinese hamster ovary cells after treatment with paclitaxel
(Taxol) and other microtubule interacting agents has been investigated.
Using a trans-reporting system, the phosphorylation of
the nuclear transcription factors Elk-1 and c-jun was measured. Concentration- and time-dependent activation of the Elk-1 pathway, mediated primarily by the extracellular signal-regulated kinase (ERK)
component of the MAPK family, was observed. Inactive drug analogs and
other cytotoxic compounds that do not target microtubules failed to
induce similar levels of activation, thereby indicating that an
interaction between these drugs and the microtubule is essential for
the activation of MAPKs. Evaluation of the endogenous levels of MAPK
expression revealed cell-dependent expression of the ERK, c-jun
N-terminal kinase, and p38 pathways. In the case of HeLa cells,
time-dependent activation of ERK coincided with increased
poly(ADP-ribose) polymerase (PARP) cleavage, phosphatidylserine externalization, and increased accumulation of cells in
G2M. In both cell lines, inhibition of ERK activity
potentiated paclitaxel-induced PARP cleavage and phosphatidylserine
externalization, suggesting that ERK activity coincided with, but did
not mediate, the cytotoxic effects of paclitaxel. We evaluated the
nature of the interaction between paclitaxel and the MAPK kinase
inhibitor U0126 in three cell lines, on the basis of a potential
chemotherapeutic advantage of paclitaxel plus ERK inhibition. Our data
confirmed additivity in those cells lines that undergo
paclitaxel-induced ERK activation, and antagonism in cells with low ERK
activity, suggesting that in tumors with high ERK activity, there may
be an application for this strategy in therapy.
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