2. Academic Validation
  3. Neddylation signaling inactivation by tetracaine hydrochloride suppresses cell proliferation and alleviates vemurafenib-resistance of melanoma

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

  • Cell Biol Toxicol. 2024 Sep 19;40(1):81. doi: 10.1007/s10565-024-09916-y.
Xiang Huang # 1 2 3,  Peng Yi # 1 2,  Wanrong Gou 1 2,  Ran Zhang 1 2,  Chunlin Wu 1,  Li Liu 1 2,  Yijing He 4,  Xian Jiang 1 5,  Jianguo Feng 6 7
Affiliations

Affiliations

  • 1 Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, Sichuan Province, China.
  • 2 Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, Sichuan Province, China.
  • 3 Department of Anesthesiology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, Guizhou Province, China.
  • 4 Laboratory of Nervous System Disease and Brain Functions, Clinical Research Institute, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan Province, China.
  • 5 Department of Anesthesiology, Luzhou People's Hospital, Luzhou, 646000, Sichuan Province, China.
  • 6 Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, Sichuan Province, China. fengjianguo@swmu.edu.cn.
  • 7 Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, Sichuan Province, China. fengjianguo@swmu.edu.cn.
  • # Contributed equally.
PMID: 39297891 DOI: 10.1007/s10565-024-09916-y
Abstract

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.

Keywords

Local anesthetics; Melanoma; Neddylation; Tetracaine hydrochloride; Vemurafenib-resistance.

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