Regulators on expression of genes associated with anticancer drug resistance

目前有关抗癌药物耐药相关基因表达调控的报道较少。已有报道表明，p53和RAS基因可调控mdr1基因的表达。然而，这些基因产物在人髓系白血病细胞系KY-821及其耐药亚系中没有核内表达的证据。推测在这些细胞系中存在核因子-kappaB或AP-1转录因子的交替表达，因为已经存在肿瘤坏死因子α(TNFα)对这些细胞系的细胞生长的交替调节。KY-821细胞核内核转录因子-kappaB的表达随肿瘤坏死因子α浓度的增加而增强，而耐药细胞株的核内核转录因子-kappaB的表达无明显变化。而耐药细胞系中对肿瘤坏死因子α敏感的亚克隆在肿瘤坏死因子α刺激后表达高水平的核因子-kappaB。另一种转录因子AP-1在肿瘤坏死因子α刺激后，在KY-821及其耐药亚系中均增强，提示与肿瘤坏死因子α耐药和抗癌药物耐药无关。此外，YB-1在本研究使用的细胞系中不表达，尽管YB-1最近被报道为mdr1基因的调节因子。另一方面，热休克蛋白27(HSP27)和热休克蛋白70(HSP70)在人卵巢癌顺铂耐药细胞株Tyk-R10胞核中表达，但不表达mdr1基因，表现出多药耐药特性。热休克处理提高了HSPs的表达水平和耐药水平。因此，需要进一步的检查来阐明包括热休克蛋白在内的哪些转录因子与耐药密切相关。

There are few reports on the regulation of the expression of the genes associated with resistance of the anticancer drugs. The previous reports demonstrated that p53 and RAS genes colud regulate the expression of MDR1 gene. However, there was no evidence of intranuclear expression of these gene products in human myelogenous leukemia cell line, KY-821 as well as its drug resistant sublines. Alternative expression of NF-kappaB or AP-1 transcription factors is speculated in these cell lines, because alternative regulation of cells growth of these cell lines with tumor necrosis factor alpha (TNF alpha) has been present. The expression of intranuclear NF-kappaB was enhanced with TNF alpha in KY-821, while it was not changed in drug resistant sublines. However, TNF alpha sensitive subclones of drug resistant cell lines expressend high level NF-kappaB after stimulation with TNF alpha. One of the other transcription factors, AP-1, was enhanced in both KY-821 and its drug resistant sublines after TNF alpha stimulation, indicating no association with resistance to TNF alpha and anticancer drugs. Furthermore, YB-1 is not expressed in cell lines used in this study, although YB-1 has been recently reported as a regulator of MDR1 gene. On the other hand, heat shock protein 27 (HSP27) and HSP70 have been expressed in the nucleus of cisplatin resistant human ovarian carcinoma cell line, TYK-R10, with showed multidrug resistant characteristics without MDR1 gene expression. Heat shock treatment enhanced the expression of HSPs as well as drug resistant level. Thus further examinations should be needed to elucidate what transcripton factors including HSPs are closely associated with drug resistance.