Journal Article

Local anesthetics impair the growth and self-renewal of glioblastoma stem cells by inhibiting ZDHHC15-mediated GP130 palmitoylation

Wang, Delong, Fang, Zhiyou, Zhao, Chenggang, Fan, Xiaoqing, Chen, Xueran, Wang, Ruiting, Yang, Haoran, Hu, Lizhu

2021

Overview

Background 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. Methods 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. Results 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. Conclusions In conclusion, our work emphasizes that ZDHHC15 is a candidate therapeutic target, and local anesthetics are potential therapeutic options for glioblastoma.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Analysis / Anesthetics / Anesthetics, Local - pharmacology / Antibodies / Benzocaine / Biomedical and Life Sciences / Biomedical Engineering and Bioengineering / Biotin / Brain cancer / Brain Neoplasms / Bupivacaine / Cancer therapies / Cell Biology / Cell Line, Tumor / Cell migration / Cell Proliferation / Cell self-renewal / Cell survival / Cloning / Cytokine Receptor gp130 - metabolism / DNA binding proteins / Drug resistance / Glioblastoma / Glioblastoma - drug therapy / Glioblastoma - genetics / Glioblastoma multiforme / Glioblastoma stem cells / Glioma / Glycoprotein gp130 / GP130 / Growth factors / Health aspects / Humans / Immunofluorescence / Immunoprecipitation / Interleukin 6 / Lidocaine / Life Sciences / Lipoylation / Local anesthesia / Local anesthetics / Localization / Mass spectrometry / Mass spectroscopy / Medical prognosis / Molecular modelling / Neoplastic Stem Cells - metabolism / Palmitoylation / Palmitoyltransferase / Phenotypes / Prilocaine / Proteins / Regenerative Medicine/Tissue Engineering / Ropivacaine / Self-renewal / STAT3 / Stat3 protein / Stem Cells / Therapeutic targets / Tumorigenesis / Xenografts / ZDHHC15 / Zinc finger proteins