七氟醚通过组蛋白去乙酰化酶 6 调节体外促进宫颈癌细胞的增殖、转移潜能。
Sevoflurane Enhances Proliferation, Metastatic Potential of Cervical Cancer Cells via the Histone Deacetylase 6 Modulation In Vitro.
机构信息
From the Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China (W.Z., B.S., S.C., X.Z.) Anesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom (W.Z., H.Z., L.W., Y.S., J.C., D.M.) the Department of Anesthesiology and Critical Care Medicine, Peking University First Hospital, Beijing, China (Y.S.).
出版信息
Anesthesiology. 2020 Jun;132(6):1469-1481. doi: 10.1097/ALN.0000000000003129.
BACKGROUND
Sevoflurane is commonly used for cervical cancer surgery, but its effect on cervical cancer cell biology remains unclear. This mechanistic study explores how sevoflurane affects the proliferation and metastatic potential of immortalized cervical cancer cell lines.
METHODS
Cultured cervical cancer Caski and HeLa lines were exposed to 1, 2, or 3% sevoflurane for 2 or 4 h. Cell proliferation was determined through the Kit-8 assay and Ki-67 immunofluorescent staining. Cell migration and invasion were evaluated with the Transwell assay. Immunofluorescent staining and Western blot analysis were used to identify sevoflurane-induced morphological and biochemical changes.
RESULTS
Sevoflurane exposure for either 2 or 4 h significantly increased HeLa cell proliferation in a time- and concentration-dependent manner to be 106 ± 2.7% and 107 ± 1.4% relative to the controls (n = 10; P = 0.036; P = 0.022) at 24 h after exposure and to be 106 ± 2.2% and 106 ± 1.7% relative to the controls (n = 10; P = 0.031; P = 0.023) at the highest concentration of 3% sevoflurane studied, respectively, but not Caski cells. Sevoflurane promoted invasion ability (1.63 ± 0.14 and 1.92 ± 0.12 relative to the controls) and increased cell size (1.69 ± 0.21 and 1.76 ± 0.13 relative to the controls) of Caski and HeLa cells (n = 6; all P < 0.001), respectively. Sevoflurane increased histone deacetylase 6 expression in both cells, and histone deacetylase 6 knockdown abolished the prometastatic effects of sevoflurane. Sevoflurane also induced deacetylation of α-tubulin in a histone deacetylase 6-dependent manner. The protein kinase B (AKT) or extracellular regulated protein kinase (ERK1/2) phosphorylation inhibition attenuated sevoflurane-induced histone deacetylase 6 expression.
CONCLUSIONS
Sevoflurane enhanced proliferation, migration, and invasion of immortalized cervical cancer cells, which was likely associated with increasing histone deacetylase 6 expression caused by phosphatidylinositide 3-kinase/AKT- and ERK1/2-signaling pathway activation.
背景
七氟醚常用于宫颈癌手术，但它对宫颈癌细胞生物学的影响尚不清楚。本机制研究探讨了七氟醚如何影响永生化宫颈癌细胞系的增殖和转移潜能。
方法
将培养的宫颈癌 Caski 和 HeLa 细胞分别暴露于 1%、2%或 3%七氟醚中 2 或 4 小时。通过 Kit-8 测定和 Ki-67 免疫荧光染色来确定细胞增殖。通过 Transwell 测定评估细胞迁移和侵袭。免疫荧光染色和 Western blot 分析用于鉴定七氟醚诱导的形态和生化变化。
结果
暴露于 2 或 4 小时的七氟醚均以时间和浓度依赖性方式显著增加 HeLa 细胞的增殖，在暴露后 24 小时相对于对照组分别为 106 ± 2.7%和 107 ± 1.4%（n = 10；P = 0.036；P = 0.022），且在研究的最高浓度 3%七氟醚下分别为 106 ± 2.2%和 106 ± 1.7%相对对照组（n = 10；P = 0.031；P = 0.023），但对 Caski 细胞无影响。七氟醚促进 Caski 和 HeLa 细胞的侵袭能力（相对于对照组分别为 1.63 ± 0.14 和 1.92 ± 0.12），并增加细胞大小（相对于对照组分别为 1.69 ± 0.21 和 1.76 ± 0.13）（n = 6；均 P < 0.001）。七氟醚增加了两种细胞中的组蛋白去乙酰化酶 6 的表达，而组蛋白去乙酰化酶 6 敲低消除了七氟醚的促转移作用。七氟醚还以组蛋白去乙酰化酶 6 依赖性方式诱导α-微管蛋白去乙酰化。蛋白激酶 B（AKT）或细胞外调节蛋白激酶（ERK1/2）磷酸化抑制剂减弱了七氟醚诱导的组蛋白去乙酰化酶 6 表达。
结论
七氟醚增强了永生化宫颈癌细胞的增殖、迁移和侵袭，这可能与磷酸肌醇 3-激酶/AKT 和 ERK1/2 信号通路激活引起的组蛋白去乙酰化酶 6 表达增加有关。
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