c-Jun NH2-terminal
protein kinase (JNK), a member of the
mitogen-activated protein kinase family, is activated in response to many stressful stimuli including heat shock, UV irradiation,
protein synthesis inhibitors, and inflammatory
cytokines. In this study, we investigated whether JNK plays a role in the cellular response to different drugs commonly used in
cancer chemotherapy. Treatment of human KB-3
carcinoma cells with
Adriamycin resulted in a time- and dose-dependent activation of JNK of up to 40-fold. Treatment with
vinblastine or
etoposide (VP-16) also activated JNK, with maximum increases of 6.5- and 4.3-fold, respectively. Consistent with these findings, increased c-Jun phosphorylation was observed after
drug treatment of cells. In contrast, none of the drugs significantly activated the extracellular response
kinase/mitogen-activated protein kinase pathway. Since these drugs are transport substrates for the MDR1 gene product,
P-glycoprotein, JNK was assayed in two multidrug-resistant (MDR) KB cell lines, KB-A1 and KB-V1, selected for resistance to
Adriamycin and
vinblastine, respectively. Relative to KB-3 cells, basal JNK activity was increased 7-fold in KB-A1 cells and 4-fold in KB-V1 cells, with no change in JNK
protein expression, indicating that JNK is present in a more highly activated form in the MDR cell lines. Under conditions optimal for JNK activation,
Adriamycin,
vinblastine, and
VP-16 all induced MDR1
mRNA expression in KB-3 cells. Our findings suggest that JNK activation is an important component of the cellular response to several structurally and functionally distinct anticancer drugs and may also play a role in the MDR phenotype.