Lf. Lee et al., PACLITAXEL (TAXOL)-INDUCED GENE-EXPRESSION AND CELL-DEATH ARE BOTH MEDIATED BY THE ACTIVATION OF C-JUN NH2-TERMINAL KINASE (JNK SAPK)/, The Journal of biological chemistry, 273(43), 1998, pp. 28253-28260
Paclitaxel (Taxol) is a novel anti-cancer drug that has shown efficacy
toward several malignant tumors, particularly ovarian tumors. We repo
rted previously that paclitaxel can induce interleukin IL-8 promoter a
ctivation in subgroups of ovarian cancer through the activation of bot
h AP-1 and nuclear factor kappa B. Further analysis of paclitaxel anal
ogs indicates that the degree of IL-8 induction by analysis correlates
with the extent of cell death; however, IL-8 itself is not the cause
of cell death. This suggests that pathways that lead to IL-8 and cell
death may overlap, although IL-8 per se does not kill tumor cells. To
decipher the upstream signals for paclitaxel-induced transcriptional a
ctivation and cell death, we studied the involvement of protein kinase
s that lead to the activation of AP-1, specifically the c-Jun NH2-term
inal kinase (JNK1), p38, and the extracellular signal-regulated kinase
1 (ERK1). The role of I kappa B in paclitaxel-induced cell death was
also analyzed. Paclitaxel activated JNK, and to a lesser degree p38, b
ut not ERK1. Paclitaxel-induced IL-8 promoter activation was inhibited
by dominant-inhibitory mutants of JNK p38, and the super-repressor fo
rm of I kappa B alpha, but not by dominant-inhibitory forms of ERK1. D
ominant-inhibitory mutants of JNK1 also greatly reduced paclitaxel-ind
uced cell death, and the kinetics of JNK induction was closely followe
d by DNA fragmentation. These results indicate (i) that paclitaxel act
ivates the JNK signaling pathway and (ii) that JNK activation is a com
mon point of paclitaxel-induced gene induction and cell death.