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Neddylation signaling inactivation by tetracaine hydrochloride suppresses cell proliferation and alleviates vemurafenib-resistance of melanoma

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机构: [1]Department of Anesthesiology, The Afliated Hospital, Southwest Medical University, Luzhou 646000, Sichuan Province, China [2]Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, The Afliated Hospital, Southwest Medical University, Luzhou 646000, Sichuan Province, China [3]Department of Anesthesiology, Afliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China [4]Laboratory of Nervous System Disease and Brain Functions, Clinical Research Institute, The Afliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan Province, China [5]Department of Anesthesiology, Luzhou People’s Hospital, Luzhou 646000, Sichuan Province, China
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关键词: Local anesthetics Melanoma Neddylation Tetracaine hydrochloride Vemurafenib-resistance

摘要:
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).

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大类 | 2 区 医学
小类 | 1 区 毒理学 3 区 细胞生物学
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第一作者机构: [1]Department of Anesthesiology, The Afliated Hospital, Southwest Medical University, Luzhou 646000, Sichuan Province, China [2]Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, The Afliated Hospital, Southwest Medical University, Luzhou 646000, Sichuan Province, China [3]Department of Anesthesiology, Afliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China
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