Radicicol potentiates heat-induced cell killing in a human oesophageal cancer cell line: the Hsp90 chaperone complex as a new molecular target for enhancement of thermosensitivity
Radicicol potentiates heat-induced cell killing in a human oesophageal cancer cell line: the Hsp90 chaperone complex as a new molecular target for enhancement of thermosensitivity
复制标题
DOI：
10.1080/09553000410001725107
复制
发表时间：
2004-07-01
影响因子：
2.6
通讯作者：
Mitsuhashi, N
中科院分区：
文献类型：
--
作者：
Akimoto, T;Nonaka, T;Mitsuhashi, N
目的：检测热休克蛋白90(Hsp90)分子伴侣复合体抑制剂自由基对热反应和热诱导细胞杀伤的影响，并阐明其作用机制。材料和方法：以人食道癌细胞株(TE-1)为实验对象，检测突变型p53基因。为了检测自由基对热诱导的细胞杀伤的影响，将100 nM的自由基与细胞在热处理过程中孵育7h。结果：尽管自由基醇引起HSP72和HSP27的表达增加，但联合应用热能协同增强热诱导的细胞杀伤作用。热单独激活Raf-1和p42/p44细胞外信号调节激酶(ERK)，而热与自由基醇结合通过减少Raf-1与Hsp90的结合而抑制Raf-1和p42/p44Erk的激活。结论：Hsp90分子伴侣复合体抑制剂，自由基，增强热诱导的细胞杀伤，抑制p42/p44Erk和Akt的激活，而不是改变HSP的表达，可能与增强细胞的热敏感性有关。结果提示，Hsp90分子伴侣复合体可能是细胞热反应修饰的一个新的分子靶点。
Purpose: To examine the ability of a heat shock protein 90 (Hsp90) chaperone complex inhibitor, radicicol, to modify thermal response and heat-induced cell killing, and to clarify the underlining mechanisms.Materials and methods: A human oesophageal cancer cell line (TE-1), with a mutant p53 gene, was used. To examine the effect of radicicol on heat-induced cell killing, radicicol at a concentration of 100 nM was incubated with the cells for 7 h during heat treatment. Changes in the expression of proteins were examined by Western blot and immunofluorescence analysis.Results: Radicicol in combination with heat synergistically potentiated heat-induced cellular killing despite an increase in the expression of Hsp72 and Hsp27 caused by radicicol. Heat alone activated Raf-1 and p42/p44 extracellular signal-regulated kinase(Erk), and heat in combination with radicicol inhibited the activation of Raf-1 and p42/p44 Erk through reduced binding of Raf-1 to Hsp90. Phosphorylation of Akt was also decreased by radicicol.Conclusions: The Hsp90 chaperone complex inhibitor, radicicol, potentiated heat-induced cellular killing, and inhibition of p42/p44 Erk and Akt activation rather than modification of Hsp expression might be involved in enhancing cellular thermosensitivity. Results suggest that the Hsp90 chaperone complex could be a new molecular target for the modification of the cellular response to heat.