Shen J W, Subjeck J R, Lock R B, Ross W E
Division of Radiation Biology, Roswell Park Memorial Institute, Buffalo, New York 14263.
Mol Cell Biol. 1989 Aug;9(8):3284-91. doi: 10.1128/mcb.9.8.3284-3291.1989.
Conditions, such as anoxia or glucose starvation, which induce the glucose-regulated set of stress proteins also lead to resistance to adriamycin (J. Shen, C. Hughes, C. Chao, J. Cai, C. Bartels, T. Gessner, and J. Subjeck, Proc. Natl. Acad. Sci. USA 84:3278-3282, 1987) and etoposide. We report here that chronic anoxia, glucose starvation, 2-deoxyglucose, the calcium ionophore A23187, glucosamine, ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), and tunicamycin (all specific inducers of the glucose regulated system) lead to a rapid and selective depletion of topoisomerase II from isolated nuclei of Chinese hamster ovary cells. This effect precedes a decline in tritiated thymidine incorporation and a redistribution of cells from S into G1/G0. The depletion of the enzyme is not accompanied by a decline in mRNA levels. We have also examined the mutant Chinese hamster K12 cell line which is temperature sensitive for expression of glucose-regulated proteins. When nuclei were isolated from K12 cells incubated at the nonpermissive temperature, a loss of topoisomerase II was again observed in congruence with the expression of stress proteins and cellular resistance to etoposide. These changes were not obtained in parental Wg1A cells incubated at the same temperature. These studies indicate that topoisomerase II is highly sensitive to glucose-regulated stresses and that its depletion from the nucleus, with the associated changes in cell cycle parameters, may represent general characteristics of the glucose-regulated state. Since anoxia and glucose starvation can occur during tumor development, this pathway for expression of drug resistance may have clinical ramifications.
诸如缺氧或葡萄糖饥饿等可诱导产生一组葡萄糖调节应激蛋白的条件，也会导致对阿霉素（J. 沈、C. 休斯、C. 赵、J. 蔡、C. 巴特尔、T. 格斯纳和J. 苏贝克，《美国国家科学院院刊》84:3278 - 3282，1987年）和依托泊苷产生抗性。我们在此报告，慢性缺氧、葡萄糖饥饿、2 - 脱氧葡萄糖、钙离子载体A23187、氨基葡萄糖、乙二醇双（β - 氨基乙基醚）- N,N,N',N'- 四乙酸（EGTA）和衣霉素（均为葡萄糖调节系统的特异性诱导剂）会导致从中国仓鼠卵巢细胞分离的细胞核中拓扑异构酶II迅速且选择性地耗竭。这种效应先于氚标记胸腺嘧啶掺入量的下降以及细胞从S期重新分布到G1/G0期。该酶的耗竭并未伴随着mRNA水平的下降。我们还研究了对葡萄糖调节蛋白表达具有温度敏感性的突变中国仓鼠K12细胞系。当从在非允许温度下培养的K12细胞中分离细胞核时，再次观察到拓扑异构酶II的丢失，这与应激蛋白的表达以及细胞对依托泊苷的抗性一致。在相同温度下培养的亲本Wg1A细胞中未出现这些变化。这些研究表明拓扑异构酶II对葡萄糖调节应激高度敏感，并且其从细胞核中的耗竭以及相关的细胞周期参数变化可能代表了葡萄糖调节状态的一般特征。由于缺氧和葡萄糖饥饿可能在肿瘤发展过程中发生，这种耐药性表达途径可能具有临床意义。
