Chemical chaperone therapy for anaplastic thyroid carcinoma

突变型P53(Mp53)肿瘤患者的预后通常比野生型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，以恢复突变蛋白的功能，使其恢复到野生型蛋白的功能。然后，我们研究了甘油的化学伴侣对mp53肿瘤细胞的修复作用。使用携带mP53基因的间变性甲状腺癌细胞系(8305c)。在培养中，甘油处理的8305c细胞对CDDP更敏感。此外，只有在甘油和顺铂处理的细胞中才能观察到凋亡小体和DNA梯状条带。此外，还探讨了利用DNA阵列和蛋白质芯片进行化学伴侣治疗的机制。甘油处理细胞后，TRAF2、NIK、IKK、NFkB和IAP等凋亡抑制基因的mRNA表达降低。在蛋白质水平上，这些蛋白的表达也有所下降。这些结果表明，不仅P53通路，而且NFkB通路与使用甘油的化学伴侣疗法有很深的关系。此外，在移植了肿瘤的裸鼠中，当用甘油和CDDP治疗肿瘤时，观察到肿瘤生长明显延迟。因此，我们期望化学伴侣疗法将为mp53肿瘤的癌症治疗提供一种新的策略。

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.