Kurata Morito, Abe Shinya, Suzuki Shiho, Li Na, Ohnishi Iichiro, Hasegawa Maki, Yamamoto Kouhei, Kitagawa Masanobu
Department of Comprehensive Pathology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
J Med Dent Sci. 2011 Jul 4;58(2):85-8.
Radiation therapy, inducing DNA damage, is one of the most effective tools for treatments of human cancers, but the effectiveness of the therapy is largely depending on the host specific conditions. Recently genetic constitution has proven to be important for apoptosis-induction responding to DNA damage. Regarding the host-specific manner of responses against DNA-damage in animal model, we have reported that infection with Friend leukemia virus (FLV) enhances the DNA damage-induced apoptosis in hematopoietic cells derived from C3H but DBA/2 mice. Furthermore, p53 or ATM knockout mice of C3H background and DNA-PK-deficient C3H SCID mice did not show the enhanced apoptosis by FLV. Recently, we could show that this host-specific apoptosis was mediated by the kinase activity of DNA-PK in association with FLV env-coding protein, gp70. Interestingly, two host proteins, acinus and MCM2, were also associated with DNA-PK and gp70 and were host-specifically overexpressed in C3H-derived cells. Our data suggest that gp70 enhances cellular DNA damage-induced signaling in association with host-specific cellular proteins, including acinus and MCM2, resulting in the activation of DNA-PK to phosphorylate P53. By introducing gp70/acinus/MCM2-associated pathways into tumor cells, cancer therapy with DNA damage-inducing agents might become much more effective. Our aim is to develop a novel form of targeted therapy that can be combined with other treatment modalities, such as radiotherapy and chemotherapy, using the host-specific regulatory mechanisms of apoptotic enhancement.
放射疗法可诱导DNA损伤，是治疗人类癌症最有效的工具之一，但该疗法的有效性很大程度上取决于宿主的特定条件。最近，基因构成已被证明对DNA损伤诱导的细胞凋亡反应很重要。关于动物模型中针对DNA损伤的宿主特异性反应方式，我们报道过，感染弗瑞德白血病病毒（FLV）可增强源自C3H而非DBA/2小鼠的造血细胞中DNA损伤诱导的细胞凋亡。此外，C3H背景的p53或ATM基因敲除小鼠以及DNA-PK缺陷的C3H SCID小鼠并未表现出FLV诱导的细胞凋亡增强。最近，我们发现这种宿主特异性细胞凋亡是由DNA-PK的激酶活性与FLV包膜编码蛋白gp70共同介导的。有趣的是，两种宿主蛋白，腺泡蛋白和微小染色体维持蛋白2（MCM2），也与DNA-PK和gp70相关，并在源自C3H的细胞中宿主特异性过表达。我们的数据表明，gp70与包括腺泡蛋白和MCM2在内的宿主特异性细胞蛋白共同增强细胞DNA损伤诱导的信号传导，从而导致DNA-PK激活以磷酸化p53。通过将gp70/腺泡蛋白/MCM2相关途径引入肿瘤细胞，使用DNA损伤诱导剂的癌症治疗可能会变得更加有效。我们的目标是利用凋亡增强的宿主特异性调节机制，开发一种可与放疗和化疗等其他治疗方式联合使用的新型靶向治疗方法。
