Osborn M T, Chambers T C
Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205-7199, USA.
J Biol Chem. 1996 Nov 29;271(48):30950-5. doi: 10.1074/jbc.271.48.30950.
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.
c-Jun氨基末端蛋白激酶（JNK）是丝裂原活化蛋白激酶家族的成员之一，可响应多种应激刺激而被激活，这些刺激包括热休克、紫外线照射、蛋白质合成抑制剂和炎性细胞因子。在本研究中，我们调查了JNK在细胞对癌症化疗常用的不同药物的反应中是否发挥作用。用阿霉素处理人KB-3癌细胞导致JNK呈时间和剂量依赖性激活，激活倍数高达40倍。用长春碱或依托泊苷（VP-16）处理也可激活JNK，最大增幅分别为6.5倍和4.3倍。与这些发现一致，在药物处理细胞后观察到c-Jun磷酸化增加。相比之下，这些药物均未显著激活细胞外信号调节激酶/丝裂原活化蛋白激酶途径。由于这些药物是MDR1基因产物P-糖蛋白的转运底物，因此在分别对阿霉素和长春碱耐药的两种多药耐药（MDR）KB细胞系KB-A1和KB-V1中检测了JNK。相对于KB-3细胞，KB-A1细胞中基础JNK活性增加了7倍，KB-V1细胞中增加了4倍，而JNK蛋白表达没有变化，这表明JNK在MDR细胞系中以更高的激活形式存在。在最适合JNK激活的条件下，阿霉素、长春碱和VP-16均诱导KB-3细胞中MDR1 mRNA表达。我们的研究结果表明，JNK激活是细胞对几种结构和功能不同的抗癌药物反应的重要组成部分，并且可能在MDR表型中也发挥作用。
