Laboratory of Molecular Diagnostics and Therapeutics, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677-1 Yoshida, Yamaguchi, 753-8515, Japan.
Laboratory of Veterinary Internal Medicine, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677-1 Yoshida, Yamaguchi, 753-8515, Japan.
Biochem Biophys Res Commun. 2019 Sep 17;517(2):233-237. doi: 10.1016/j.bbrc.2019.07.050. Epub 2019 Jul 22.
Although reovirus has reached phase II and III clinical trials in human cancers, the exact mechanism of reovirus oncolysis is still not completely understood. Previously, we have shown that canine mast cell tumor (MCT) cell lines were highly susceptible to reovirus, as compared with other kinds of canine cancer cell lines. In this study, we showed that reovirus infection not only led to the dephosphorylation but also downregulation of c-kit in four canine MCT cell lines, where c-kit activation is required for proliferation. Consistent with c-kit dysregulation, downstream signaling of c-kit, the level of Ras-GTP and phosphorylation of all the downstream effectors of Ras (Raf, MEK, and ERK) and Akt decreased in all the cell lines after reovirus infection, except for Akt in one of cell lines. Pro-apoptotic and anti-apoptotic proteins such as Bim, Bad and Mcl-1 were also altered by reovirus infection in these cell lines. In short, reovirus infection degraded c-kit in all the canine MCT cell lines, leading to the downregulation of downstream signaling of c-kit, which may relate to the cell death induced by reovirus.
虽然呼肠孤病毒在人类癌症的 II 期和 III 期临床试验中已经取得了进展，但呼肠孤病毒溶瘤的确切机制仍不完全清楚。先前，我们已经表明，犬肥大细胞瘤（MCT）细胞系对呼肠孤病毒高度敏感，而其他犬癌细胞系则不是这样。在这项研究中，我们表明呼肠孤病毒感染不仅导致了四种犬 MCT 细胞系中 c-kit 的去磷酸化，还导致了 c-kit 的下调，而 c-kit 的激活是增殖所必需的。与 c-kit 失调一致，c-kit 的下游信号、Ras-GTP 的水平以及 Ras（Raf、MEK 和 ERK）和 Akt 的所有下游效应物的磷酸化在呼肠孤病毒感染后均降低，除了一个细胞系中的 Akt 外。促凋亡和抗凋亡蛋白，如 Bim、Bad 和 Mcl-1，也在这些细胞系中被呼肠孤病毒感染改变。总之，呼肠孤病毒感染降解了所有犬 MCT 细胞系中的 c-kit，导致 c-kit 的下游信号下调，这可能与呼肠孤病毒诱导的细胞死亡有关。
