Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
1] Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan [2] Laboratory of Hepatic Differentiation Research, National Institute of Biomedical Innovation, Osaka, Japan [3] Center for Advanced Medical Engineering and Informatics, Osaka University, Osaka, Japan [4] Laboratory of iPS Research, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Cancer Gene Ther. 2015 Mar;22(4):188-97. doi: 10.1038/cgt.2015.4. Epub 2015 Jan 30.
Reovirus has gained much attention as an anticancer agent; however, the mechanism of the tumor cell-specific replication of reovirus is not fully understood. Although Ras activation is known to be crucial for tumor cell-specific replication of reovirus, it remains controversial which cellular factors are required for the reovirus-mediated tumor cell killing. In this study, we systematically investigated which cellular factors determined the efficiencies of reovirus-mediated tumor cell killing in various human cultured cell lines. The efficiency of reovirus-mediated cell killing varied widely among the cell lines. Junction adhesion molecule-A, a reovirus receptor, was highly expressed in almost all cell lines examined. Ras activation levels were largely different between the cell lines; however, there were no apparent correlations among the reovirus-mediated cell killing efficiencies and Ras activation status. On the other hand, activity levels of the cysteine proteases cathepsins B and L, which are crucial for proteolytic disassembly of the outer capsid proteins of reovirus, showed a tendency to be correlated with the efficiency of reovirus-mediated cell killing. These results indicate that the activity of cathepsins B and L is the most suitable as a biomarker for the efficacy of reovirus-mediated oncolysis among the factors examined in this study.
呼肠孤病毒作为一种抗癌药物引起了广泛关注；然而，呼肠孤病毒对肿瘤细胞的特异性复制的机制尚未完全阐明。虽然 Ras 的激活被认为对呼肠孤病毒对肿瘤细胞的特异性复制至关重要，但对于呼肠孤病毒介导的肿瘤细胞杀伤所需的细胞因子仍存在争议。在这项研究中，我们系统地研究了哪些细胞因子决定了呼肠孤病毒在各种人培养细胞系中介导肿瘤细胞杀伤的效率。呼肠孤病毒介导的细胞杀伤效率在细胞系之间差异很大。连接黏附分子 A 是呼肠孤病毒的受体，几乎在所有检测到的细胞系中都高度表达。Ras 激活水平在细胞系之间有很大的不同；然而，呼肠孤病毒介导的细胞杀伤效率与 Ras 激活状态之间没有明显的相关性。另一方面，半胱氨酸蛋白酶组织蛋白酶 B 和 L 的活性水平，这对呼肠孤病毒外壳蛋白的蛋白水解解体至关重要，与呼肠孤病毒介导的细胞杀伤效率呈正相关。这些结果表明，在本研究中检查的因素中，组织蛋白酶 B 和 L 的活性最适合作为呼肠孤病毒介导的溶瘤作用疗效的生物标志物。
