丁卡因是一种局部麻醉剂，对多种癌症具有有效的细胞毒性作用。然而，其抗癌活性的确切潜在机制仍不确定。本研究发现丁卡因的抗癌活性是常用局部麻醉药中最有效的。丁卡因处理后，通过RNAseq技术鉴定黑色素瘤细胞中差异表达的基因，并通过京都基因和基因组百科全书富集溶酶体信号通路、cullin家族蛋白结合和蛋白酶体信号通路。此外，在黑色素瘤中过度激活的泛素样neddylation信号通路可能会因丁卡因治疗后NAE2表达降低而被消除。促癌生存素的 neddylation 增强了其稳定性，在丁卡因治疗后显着减少。 NEDD8 过表达激活的 neddylation 信号可降低丁卡因体内和体外的抗肿瘤功效。此外，维莫非尼耐药的黑色素瘤细胞表现出更高水平的neddylation，并且通过免疫沉淀和质谱法鉴定了进行neddylation修饰的潜在底物蛋白。丁卡因治疗可以通过黑色素瘤细胞中的neddylation信号通路失活来降低耐药性。这些发现表明，丁卡因通过抑制 neddylation 信号通路，有效抑制细胞增殖并减轻黑色素瘤中的维莫非尼耐药性，为控制癌症进展提供了一条有希望的途径。© 2024。作者。

Tetracaine, a local anesthetic, exhibits potent cytotoxic effects on multiple cancer; however, the precise underlying mechanisms of its anti-cancer activity remain uncertain. The anti-cancer activity of tetracaine was found to be the most effective among commonly used local anesthetics in this study. After tetracaine treatment, the differentially expressed genes in melanoma cells were identified by the RNAseq technique and enriched in the lysosome signaling pathway, cullin family protein binding, and proteasome signaling pathway through Kyoto Encyclopedia of Genes and Genomes. Additionally, the ubiquitin-like neddylation signaling pathway, which is hyperactivated in melanoma, could be abrogated due to decreased NAE2 expression after tetracaine treatment. The neddylation of the pro-oncogenic Survivin, which enhances its stability, was significantly reduced following treatment with tetracaine. The activation of neddylation signaling by NEDD8 overexpression could reduce the antitumor efficacy of tetracaine in vivo and in vitro. Furthermore, vemurafenib-resistant melanoma cells showed higher level of neddylation, and potential substrate proteins undergoing neddylation modification were identified through immunoprecipitation and mass spectrometry. The tetracaine treatment could reduce drug resistance via neddylation signaling pathway inactivation in melanoma cells. These findings demonstrate that tetracaine effectively inhibits cell proliferation and alleviates vemurafenib resistance in melanoma by suppressing the neddylation signaling pathway, providing a promising avenue for controlling cancer progression.© 2024. The Author(s).