A large number of preclinical studies have shown that local anesthetics have a direct inhibitory effect on tumor biological activities, including cell survival, proliferation, migration, and invasion. There are few studies on the role of local anesthetics in cancer stem cells. This study aimed to determine the possible role of local anesthetics in glioblastoma stem cell (GSC) self-renewal and the underlying molecular mechanisms. The effects of local anesthetics in GSCs were investigated through in vitro and in vivo assays (i.e., Cell Counting Kit 8, spheroidal formation assay, double immunofluorescence, western blot, and xenograft model). The acyl-biotin exchange method (ABE) assay was identified proteins that are S-acylated by zinc finger Asp-His-His-Cys-type palmitoyltransferase 15 (ZDHHC15). Western blot, co-immunoprecipitation, and liquid chromatograph mass spectrometer-mass spectrometry assays were used to explore the mechanisms of ZDHHC15 in effects of local anesthetics in GSCs. In this study, we identified a novel mechanism through which local anesthetics can damage the malignant phenotype of glioma. We found that local anesthetics prilocaine, lidocaine, procaine, and ropivacaine can impair the survival and self-renewal of GSCs, especially the classic glioblastoma subtype. These findings suggest that local anesthetics may weaken ZDHHC15 transcripts and decrease GP130 palmitoylation levels and membrane localization, thus inhibiting the activation of IL-6/STAT3 signaling. In conclusion, our work emphasizes that ZDHHC15 is a candidate therapeutic target, and local anesthetics are potential therapeutic options for glioblastoma.

中文翻译：

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局麻药通过抑制 ZDHHC15 介导的 GP130 棕榈酰化作用损害胶质母细胞瘤干细胞的生长和自我更新

大量临床前研究表明，局麻药对肿瘤生物活性有直接抑制作用，包括细胞存活、增殖、迁移和侵袭。关于局部麻醉剂在癌症干细胞中作用的研究很少。本研究旨在确定局部麻醉剂在胶质母细胞瘤干细胞 (GSC) 自我更新中的可能作用及其潜在的分子机制。通过体外和体内试验（即细胞计数试剂盒 8、球体形成试验、双重免疫荧光、蛋白质印迹和异种移植模型）研究了局部麻醉剂对 GSCs 的影响。酰基-生物素交换法 (ABE) 测定鉴定了被锌指 Asp-His-His-Cys 型棕榈酰转移酶 15 (ZDHHC15) S-酰化的蛋白质。蛋白质印迹，免疫共沉淀，采用液相色谱-质谱联用技术探讨 ZDHHC15 在 GSCs 局部麻醉作用中的作用机制。在这项研究中，我们确定了一种新的机制，局部麻醉剂可以通过该机制破坏胶质瘤的恶性表型。我们发现局部麻醉剂丙胺卡因、利多卡因、普鲁卡因和罗哌卡因会损害 GSCs 的存活和自我更新，尤其是经典的胶质母细胞瘤亚型。这些发现表明，局部麻醉剂可能会削弱 ZDHHC15 转录物并降低 GP130 棕榈酰化水平和膜定位，从而抑制 IL-6/STAT3 信号传导的激活。总之，我们的工作强调 ZDHHC15 是候选治疗靶点，局部麻醉剂是胶质母细胞瘤的潜在治疗选择。