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Local anesthetic tetracaine hydrochloride induces pyroptosis via caspase-3/gasdermin E in uveal melanoma

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机构： [1]Department of Anesthesiology, the Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China [2]Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, the Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China [3]Department of Anesthesiology, Suining Central Hospital, Suining, Sichuan 629000, China [4]Key Laboratory of Medical Electrophysiology, Ministry of Education, Institute of Cardiovascular Research and Institute of Metabolic Diseases, Southwest Medical University, Luzhou, Sichuan 646000, China [5]Department of Oncology, Guangxi International Zhuang Medicine Hospital, Nanning, Guangxi, China

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关键词： Gasdermin E (GSDME) Local anesthetics Tetracaine hydrochloride Pyroptosis Uveal melanoma

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Evasion of pyroptosis is an effective survival strategy employed by cancer cells to evade immune cell attacks and drug-induced cytotoxicity. Exploring potent molecules capable of inducing pyroptosis in cancer cells has significant clinical implications for the control of cancer progression. Unexpectedly, we found that the local anesthetic tetracaine hydrochloride (TTC) induced pyroptosis, specifically in uveal melanoma but not in acral or cutaneous melanoma.We investigated the effects of TTC on various melanoma cell lines and performed transcriptome sequencing of TTC-treated uveal melanoma cells. The role of gasdermin E (GSDME), an executive protein responsible for pyroptosis, was explored using CRISPR-Cas13d knockdown, caspase-3 inhibitor treatment, and western blot analysis. Differential gene expression and pathway enrichment analyses were performed. Furthermore, we used tissue microarrays to assess GSDME expression levels in melanoma tissues from different anatomical sites.TTC significantly induced pyroptosis specifically in uveal melanoma cells with high GSDME expression levels. TTC treatment could lead to GSDME cleavage by the caspase-3 in uveal melanoma C918 cells. GSDME knockdown or caspase-3 inhibition suppressed TTC-induced pyroptosis. Transcriptome analysis revealed differentially expressed genes enriched in signaling pathways related to pyroptosis, immunity, and cytokines.This study showed that the local anesthetic TTC effectively induces pyroptosis in uveal melanoma through the caspase-3/GSDME pathway, highlighting its potential application in immunotherapy. Notably, the use of TTC has potential as an agent for inducing pyroptosis and as an adjuvant anticancer therapy in uveal melanoma.Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

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大类 | 2 区

医学

小类 | 1 区药学 2 区医学：研究与实验

第一作者：

第一作者机构： [1]Department of Anesthesiology, the Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China [2]Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, the Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China

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通讯机构： [1]Department of Anesthesiology, the Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China [2]Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, the Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China [*1]Department of Anesthesiology, the Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China.

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