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.

突变体p53（MP53）肿瘤患者的预后通常比野生型p53（WTP53）肿瘤的患者更差。本研究旨在制定一种新的策略，以克服针对MP53的癌症疗法，以恢复突变蛋白的功能，从而恢复野生型蛋白质的功能。然后，我们检查了CDDP诱导的p53依赖性凋亡的恢复，该化学伴侣对MP53肿瘤细胞的化学伴侣蛋白伴侣。使用了携带MP53基因的甲状腺甲状腺癌细胞系（8305c）。在培养中，用甘油预处理的8305C细胞对CDDP更敏感。此外，仅在用甘油和CDDP处理的细胞中观察到凋亡的身体和DNA梯子形成。此外，研究了使用DNA阵列和蛋白质芯片的化学伴侣治疗的机制。当用甘油预处理细胞时，降低了抑制性抑制基因的mRNA表达，例如TRAF2，NIK，IKK，NFKB和IAP。在蛋白质水平上，这些蛋白质的表达也降低了。这些结果表明，不仅p53途径，而且NFKB途径与使用甘油的化学伴侣治疗显示了深厚的关系。此外，在用肿瘤移植的裸小鼠中，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，我们预计化学伴侣疗法将为MP53肿瘤提供新的癌症治疗策略。