Venetianer A, Pirity M, Hever-Szabo A
Inst. of Genetics, Hungarian Academy of Sciences, Szeged.
Cell Biol Int. 1994 Jun;18(6):605-15. doi: 10.1006/cbir.1994.1087.
We earlier demonstrated that hsp68 is deficiently induced upon stress in the glucocorticoid-resistant, dedifferentiated Reuber rat hepatoma clone 2 cells, but is strongly activated in the differentiated, glucocorticoid-sensitive Faza 967 cells from which clone 2 was derived. We used the two cell types to address the questions whether hsp68 is specifically involved in the development of thermotolerance and/or thermoresistance or drug resistance. Our experiments show that clone 2 cells were not protected from the killing effect of heat by pre-treatment with sodium arsenite, whereas Faza 967 cells were. These results strongly suggest a role of hsp68 in the development of thermotolerance in hepatoma cells. Stable heat-resistant variants of clone 2 cells were also isolated, where an increased basal expression of several hsps was observed together with the (at least partial) restoration of the heat-inducibility of hsp68. These results suggest that several hsps are needed to protect the critical biological processes at high temperature. The heat-resistant hepatoma cells also became resistant to several anticancer drugs. The multidrug resistance of the hepatoma variants correlates with the overexpression of the plasma membrane P-glycoprotein. Our results showing that severely stressed hepatoma cells overexpressed the mdr gene(s) raise the possibility that the P-gp may participate in protection against environmental stress such as heat.
我们之前证明，在糖皮质激素抵抗性、去分化的鲁伯大鼠肝癌克隆2细胞中，应激时hsp68诱导不足，但在克隆2细胞所源自的分化型、糖皮质激素敏感的Faza 967细胞中，hsp68被强烈激活。我们使用这两种细胞类型来探讨hsp68是否特异性参与热耐受和/或热抗性或耐药性的发展。我们的实验表明，用亚砷酸钠预处理并不能保护克隆2细胞免受热杀伤作用，而Faza 967细胞则可以。这些结果强烈表明hsp68在肝癌细胞热耐受发展中起作用。我们还分离出了克隆2细胞的稳定耐热变体，在这些变体中观察到几种热休克蛋白的基础表达增加，同时hsp68的热诱导性（至少部分）得以恢复。这些结果表明，需要几种热休克蛋白来保护高温下的关键生物学过程。耐热肝癌细胞对几种抗癌药物也产生了抗性。肝癌变体的多药耐药性与质膜P-糖蛋白的过表达相关。我们的结果表明，受到严重应激的肝癌细胞过表达mdr基因，这增加了P-糖蛋白可能参与抵御热等环境应激的可能性。
