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Inhibitory effect of heat shock proteins in apoptosis in acquisition of anticancer drug resistance

热休克蛋白对细胞凋亡在抗癌耐药性获得中的抑制作用

基本信息

批准号：
11670182
负责人：
FUKUDA Takeaki
金额：
$ 2.18万
依托单位：
Fukushima Medical University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670182/
关键词：
Shock proteins apoptosis drug resistance oligoprobe overcome of drug resistance アポトーシス anti-sense 免疫抑制剤

项目摘要

Based on the our previous research, heat shock proteins (HSPs) play a role in acquisition of drug resistance, regardless of spieces of anticancer drugs. The aim of this research is to elucidate the regulation mechanism of expression of HSPs and the role of HSPs in apoptosis pathway by RT-PCR and gel-shift methods. Furthermore anti-sense oligoprobes to HSPs and HSE have been examined to estimate the effect of overcome of drug resistance. The levels of HSE in drug resistance cell lines have not been altered in each cell line, regardless of differentiated expression of HSPs. This finding suggests that HSF but not HSE plays a role in expression of HSPs, although the exact mechanism can not be elicited in this study. To estimate the overcome effect of anti-sense oligoprobe for HSP or HSE, three of synthesized anti-sense oligoprobes, especially anti-sense oligoprobe to HSP27, showed an evident overcome effect on drug resistance. The anti-sense oligoprobe to HSP27 inhibited the expression of mRNA of HSP27 and partilly overcame the drug resistance. Interestingly this probe could overcome the TGF-β resistance as well as anticancer resistance in HACC-TG cell line which was resistant to TGF-β as well as various anti-cancer drugs. Furthermore combination with this probe and cerulenin which was an inhibitor of fatty acid snythetase, suggesting some roles of HSP27 in lipid synthesis. The other two could inhibit of expression of mRNA of HSPs but lacked the overcome effect on drug resistance. Transfection of various HSP genes failed to induce genes associated with apoptosis. However, baxmRNA was diminished in the cells transfected with HSP70 or HSP27 genes, compared with that of the parental cells. However, the exact target points of HSPs can not be elucidated in apoptosis pathway.

根据我们以往的研究，热休克蛋白（HSPs）在获得耐药性中起作用，无论是哪种抗癌药物。本研究旨在通过RT-PCR和凝胶电泳技术，探讨热休克蛋白表达的调控机制及其在细胞凋亡途径中的作用。此外，还检测了针对HSPs和HSE的反义寡核苷酸探针，以评估克服耐药性的效果。HSE在耐药细胞系中的水平在每个细胞系中没有改变，无论HSP的分化表达如何。这一发现表明HSF而不是HSE在HSPs的表达中起作用，尽管在本研究中不能得出确切的机制。为了评价HSP或HSE反义寡核苷酸探针的耐药性克服效果，合成的三种反义寡核苷酸探针，特别是HSP 27反义寡核苷酸探针，对耐药性有明显的克服作用。HSP 27反义寡核苷酸探针可抑制HSP 27 mRNA的表达，部分克服耐药性。有趣的是，该探针可以克服对TGF-β以及各种抗癌药物具有抗性的HACC-TG细胞系中的TGF-β抗性以及抗癌抗性。进一步将该探针与脂肪酸合成酶抑制剂浅蓝菌素结合，提示HSP 27在脂质合成中的某些作用。另外两种药物可抑制HSPs mRNA的表达，但对耐药性缺乏克服作用。各种HSP基因的转染未能诱导与凋亡相关的基因。然而，与亲本细胞相比，在转染HSP 70或HSP 27基因的细胞中，baxmRNA减少。然而，在细胞凋亡途径中，热休克蛋白的确切靶点尚不清楚。