PACLITAXEL (TAXOL)-INDUCED GENE-EXPRESSION AND CELL-DEATH ARE BOTH MEDIATED BY THE ACTIVATION OF C-JUN NH2-TERMINAL KINASE (JNK SAPK)/

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.