Fokstuen T, Rabo Y B, Zhou J N, Karlson J, Platz A, Shoshan M C, Hansson J, Linder S
Department of Oncology and Pathology, Karolinska Institute and Hospital, Stockholm, Sweden.
Anticancer Res. 1997 Jul-Aug;17(4A):2347-52.
Ras proteins have been implicated in transducing cellular responses to DNA damaging agents. We used BZA-5B, an inhibitor of Ras-farnesylation, to examine the role of Ras in cellular sensitivity to cisplatin. A human melanoma cell line (224) with a Gln61Arg mutation in N-ras was used for these studies. We report that BZA-5B treated cells show an increased resistance to cisplatin. BZA-5B treatment decreased the number of cells showing in situ DNA fragmentation and increased cell viability and clonogenic survival after cisplatin treatment. Further experiments showed that cisplatin induction of the immediate early genes c-jun and p21cip1 was not affected by BZA-5B. Finally, we show that cisplatin causes only weak activation of Jun N-terminal kinase (JNK) in a human melanoma cell line. We conclude that inhibition of Ras function decreases the sensitivity of human melanoma cells to cisplatin-induced cell death.
Ras蛋白参与了将细胞对DNA损伤剂的反应进行转导的过程。我们使用了Ras-法尼基化抑制剂BZA-5B来研究Ras在细胞对顺铂敏感性中的作用。这些研究使用了一种在N-ras基因中存在Gln61Arg突变的人黑色素瘤细胞系（224）。我们报告称，经BZA-5B处理的细胞对顺铂的抗性增加。BZA-5B处理减少了显示原位DNA片段化的细胞数量，并提高了顺铂处理后的细胞活力和克隆形成存活率。进一步的实验表明，顺铂诱导的即刻早期基因c-jun和p21cip1不受BZA-5B的影响。最后，我们表明顺铂在人黑色素瘤细胞系中仅引起Jun N末端激酶（JNK）的微弱激活。我们得出结论，抑制Ras功能会降低人黑色素瘤细胞对顺铂诱导的细胞死亡的敏感性。
