Tomoda Yoshitaka, Katsura Mari, Okajima Miyuki, Hosoya Noriko, Kohno Nobuoki, Miyagawa Kiyoshi
Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Int J Cancer. 2009 Jun 15;124(12):2997-3001. doi: 10.1002/ijc.24268.
The ability to predict cisplatin sensitivity in tumors has been expected to greatly improve the outcome of cancer therapy, because the drug is frequently used in a variety of tumors. Although ERCC1 and other repair proteins have been investigated as markers of cisplatin resistance, reliable markers are still needed. Here, we demonstrate that Eme1 levels can predict cisplatin sensitivity more accurately than ERCC1 or Rad51 levels in a variety of human cancer cell lines. Eme1 forms a heterodimeric protein complex with Mus81 and functions as a structure-specific endonuclease. Haploinsufficiency of Eme1 led to hypersensitivity to cisplatin in the colon cancer cell line HCT116. On the basis of this finding, we examined the relationships between levels of proteins involved in the repair of interstrand cross-links and cisplatin sensitivity in human tumor cell lines with a variety of origins. Although ERCC1, Rad51 and Mus81 levels correlated with sensitivity to some extent, the clearest correlation was observed with Eme1. Tumors with low Eme1 levels were more sensitive to the drug than tumors with high levels. This suggests that the measurement of Eme1 in tumors may be more informative for cisplatin-based chemotherapy than that of the currently available markers.
由于顺铂常用于多种肿瘤的治疗，预测肿瘤对顺铂敏感性的能力有望极大地改善癌症治疗的效果。尽管ERCC1和其他修复蛋白已作为顺铂耐药的标志物进行了研究，但仍需要可靠的标志物。在此，我们证明在多种人类癌细胞系中，Eme1水平比ERCC1或Rad51水平能更准确地预测顺铂敏感性。Eme1与Mus81形成异二聚体蛋白复合物，并作为一种结构特异性核酸内切酶发挥作用。Eme1单倍体不足导致结肠癌细胞系HCT116对顺铂超敏。基于这一发现，我们研究了具有多种起源的人类肿瘤细胞系中，参与链间交联修复的蛋白质水平与顺铂敏感性之间的关系。尽管ERCC1、Rad51和Mus81水平在一定程度上与敏感性相关，但与Eme1的相关性最为明显。Eme1水平低的肿瘤比水平高的肿瘤对该药物更敏感。这表明，在基于顺铂的化疗中，检测肿瘤中的Eme1可能比目前可用的标志物更具信息价值。
