Mitomycin C induces apoptosis in human epidural scar fibroblasts after surgical decompression for spinal cord injury.
Mitomycin C induces apoptosis in human epidural scar fibroblasts after surgical decompression for spinal cord injury.
复制标题
丝裂霉素 C 诱导脊髓损伤手术减压后人硬膜外疤痕成纤维细胞凋亡
DOI：
10.4103/1673-5374.205106
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发表时间：
2017-04
影响因子：
6.1
通讯作者：
Ge YB
中科院分区：
文献类型：
--
作者：
Sui T;Ge DW;Yang L;Tang J;Cao XJ;Ge YB
大量研究表明，手术减压后局部应用丝裂霉素C可有效减少瘢痕粘连。然而，潜在的机制仍不清楚。本研究探讨丝裂霉素C对人硬膜外瘢痕成纤维细胞增殖和凋亡的影响。不同浓度丝裂霉素C（1、5、10、20、40 μg/mL）作用于人硬膜外瘢痕成纤维细胞12、24、48小时。丝裂霉素C以剂量和时间依赖的方式抑制这些细胞的生长。丝裂霉素C上调Fas、DR4、DR5、cleaved caspase-8/9、Bax、Bim和cleaved caspase-3蛋白的表达水平，下调Bcl-2和Bcl-xL的表达。此外，caspase-8和caspase-9抑制剂（分别为Z-IETD-FMK和Z-LEHD-FMK）不能完全抑制丝裂霉素c诱导的细胞凋亡。此外，丝裂霉素C通过增加葡萄糖调节蛋白78、CAAT/增强子结合蛋白同源蛋白（CHOP）和caspase-4的表达，以剂量依赖性方式诱导内质网应激。Salubrinal显著抑制丝裂霉素c诱导的细胞活力丧失和凋亡，并伴有CHOP表达的降低。我们的研究结果支持了丝裂霉素C至少部分通过内质网应激途径诱导人硬膜外瘢痕成纤维细胞凋亡的假设。
Numerous studies have shown that topical application of mitomycin C after surgical decompression effectively reduces scar adhesion. However, the underlying mechanisms remain unclear. In this study, we investigated the effect of mitomycin C on the proliferation and apoptosis of human epidural scar fibroblasts. Human epidural scar fibroblasts were treated with various concentrations of mitomycin C (1, 5, 10, 20, 40 μg/mL) for 12, 24 and 48 hours. Mitomycin C suppressed the growth of these cells in a dose- and time-dependent manner. Mitomycin C upregulated the expression levels of Fas, DR4, DR5, cleaved caspase-8/9, Bax, Bim and cleaved caspase-3 proteins, and it downregulated Bcl-2 and Bcl-xL expression. In addition, inhibitors of caspase-8 and caspase-9 (Z-IETD-FMK and Z-LEHD-FMK, respectively) did not fully inhibit mitomycin C-induced apoptosis. Furthermore, mitomycin C induced endoplasmic reticulum stress by increasing the expression of glucose-regulated protein 78, CAAT/enhancer-binding protein homologous protein (CHOP) and caspase-4 in a dose-dependent manner. Salubrinal significantly inhibited the mitomycin C-induced cell viability loss and apoptosis, and these effects were accompanied by a reduction in CHOP expression. Our results support the hypothesis that mitomycin C induces human epidural scar fibroblast apoptosis, at least in part, via the endoplasmic reticulum stress pathway.