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Chemical chaperone therapy for anaplastic thyroid carcinoma

化学伴侣治疗甲状腺未分化癌

基本信息

批准号：
14571628
负责人：
YANE Katsunari
金额：
$ 2.24万
依托单位：
Nara Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

项目摘要

Patients with mutant p53 (mp53) tumors often display a worse prognosis than those with wild-type p53 (wtp53) tumors. The present study aimed to develop a novel strategy for overcoming this problem in mp53-targeting cancer therapy to restore the function of mutated proteins to that of wild-type proteins. We then examined restoration of CDDP-induced p53-dependent apoptosis by a chemical chaperone of glycerol against mp53 tumor cells. An anaplastic thyroid carcinoma cell line (8305c) carrying the mp53 gene was used. In culture, 8305c cells pretreated with glycerol became more sensitive to CDDP. Moreover, apoptotic bodies and DNA ladder formation were observed only in cells treated with glycerol and CDDP. Furthermore, the mechanisms of chemical chaperone therapy using DNA arrays and protein chips were investigated. When cells were pretreated with glycerol, mRNA expression for apoptosis-suppressive genes such as TRAF2,NIK,IKK,NFkB, and IAP was decreased. At the protein level, expression of these proteins was also decreased. These results suggest that not only p53 pathways but also NFkB pathways display deep relationships with chemical chaperone therapy using glycerol. Furthermore, in nude mice transplanted with tumors, clear delays in tumor growth were observed when tumors were treated with glycerol and CDDP. We thus expect chemical chaperone therapy to offer a new strategy for cancer therapy in mp53 tumors.

突变型p53（mp53）肿瘤患者的预后往往比野生型p53（wtp53）肿瘤患者更差。本研究旨在开发一种新的策略来克服mp53靶向癌症治疗中的这一问题，以将突变蛋白的功能恢复到野生型蛋白的功能。然后，我们研究了恢复CDDP诱导的p53依赖性细胞凋亡的化学分子伴侣甘油对mp53肿瘤细胞。使用携带mp53基因的未分化甲状腺癌细胞系（8305c）。在培养中，甘油预处理的8305c细胞对CDDP更敏感。此外，仅在甘油和CDDP处理的细胞中观察到凋亡小体和DNA梯状条带形成。此外，还利用DNA芯片和蛋白质芯片研究了化学分子伴侣治疗的机制。当细胞用甘油预处理时，凋亡抑制基因如TRAF2、NIK、IKK、NFkB和IAP的mRNA表达降低。在蛋白质水平上，这些蛋白质的表达也降低。这些结果表明，不仅p53途径，而且NFkB途径显示与使用甘油的化学分子伴侣治疗有很深的关系。此外，在移植有肿瘤的裸鼠中，当用甘油和CDDP处理肿瘤时，观察到肿瘤生长的明显延迟。因此，我们期望化学分子伴侣疗法为mp53肿瘤的癌症治疗提供新的策略。