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Adrenergic Blockade by Nebivolol to Suppress Oral Squamous Cell Carcinoma Growth via Endoplasmic Reticulum Stress and Mitochondria Dysfunction

Adrenergic nerve fibers in the tumor microenvironment promote tumor growth and represent a potential target for cancer therapy. However, the effectiveness of targeting adrenergic nerve fibers for oral squamous cell carcinoma (OSCC) therapy needs to be evaluated by preclinical data. Herein, the 4NQO-...

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Autores principales: Chen, Qian, Jiang, Han, Wang, Zhen, Cai, Lu-Yao, Jiang, Yu-Chen, Xie, Liang, Zhou, Yu, Zeng, Xin, Ji, Ning, Shen, Ying-Qiang, Chen, Qian-Ming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387679/
https://www.ncbi.nlm.nih.gov/pubmed/34456721
http://dx.doi.org/10.3389/fphar.2021.691998
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author Chen, Qian
Jiang, Han
Wang, Zhen
Cai, Lu-Yao
Jiang, Yu-Chen
Xie, Liang
Zhou, Yu
Zeng, Xin
Ji, Ning
Shen, Ying-Qiang
Chen, Qian-Ming
author_facet Chen, Qian
Jiang, Han
Wang, Zhen
Cai, Lu-Yao
Jiang, Yu-Chen
Xie, Liang
Zhou, Yu
Zeng, Xin
Ji, Ning
Shen, Ying-Qiang
Chen, Qian-Ming
author_sort Chen, Qian
collection PubMed
description Adrenergic nerve fibers in the tumor microenvironment promote tumor growth and represent a potential target for cancer therapy. However, the effectiveness of targeting adrenergic nerve fibers for oral squamous cell carcinoma (OSCC) therapy needs to be evaluated by preclinical data. Herein, the 4NQO-induced and orthotopic xenograft OSCC mice models were established. We demonstrated that using 6OHDA chemical denervation as well as using nebivolol adrenergic blockade could halt the oral mucosa carcinogenesis. Our preclinical studies suggested that nebivolol, which is widely used to treat cardiovascular diseases, can be repositioned as a potential candidate to treat OSCC. Remarkably, we revealed the precise effect and mechanism of nebivolol on OSCC cells proliferation, cell cycle, and cell death. Administration of nebivolol could activate the endoplasmic reticulum (ER) stress signaling pathway through increasing the expression of inducible nitric oxide synthase, which subsequently triggers the integrated stress response and cell growth arrest. Simultaneously, ER stress also induced mitochondrial dysfunction in OSCC cells. We found that the accumulation of dysfunctional mitochondria with the impaired electron transport chain caused increasing reactive oxygen species production, which ultimately resulted in OSCC cell death. Altogether, our finding suggested a novel therapeutic opportunity for OSCC by targeting adrenergic nerve fibers, and repurposing nebivolol to treat OSCC can be represented as an effective strategy.
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spelling pubmed-83876792021-08-27 Adrenergic Blockade by Nebivolol to Suppress Oral Squamous Cell Carcinoma Growth via Endoplasmic Reticulum Stress and Mitochondria Dysfunction Chen, Qian Jiang, Han Wang, Zhen Cai, Lu-Yao Jiang, Yu-Chen Xie, Liang Zhou, Yu Zeng, Xin Ji, Ning Shen, Ying-Qiang Chen, Qian-Ming Front Pharmacol Pharmacology Adrenergic nerve fibers in the tumor microenvironment promote tumor growth and represent a potential target for cancer therapy. However, the effectiveness of targeting adrenergic nerve fibers for oral squamous cell carcinoma (OSCC) therapy needs to be evaluated by preclinical data. Herein, the 4NQO-induced and orthotopic xenograft OSCC mice models were established. We demonstrated that using 6OHDA chemical denervation as well as using nebivolol adrenergic blockade could halt the oral mucosa carcinogenesis. Our preclinical studies suggested that nebivolol, which is widely used to treat cardiovascular diseases, can be repositioned as a potential candidate to treat OSCC. Remarkably, we revealed the precise effect and mechanism of nebivolol on OSCC cells proliferation, cell cycle, and cell death. Administration of nebivolol could activate the endoplasmic reticulum (ER) stress signaling pathway through increasing the expression of inducible nitric oxide synthase, which subsequently triggers the integrated stress response and cell growth arrest. Simultaneously, ER stress also induced mitochondrial dysfunction in OSCC cells. We found that the accumulation of dysfunctional mitochondria with the impaired electron transport chain caused increasing reactive oxygen species production, which ultimately resulted in OSCC cell death. Altogether, our finding suggested a novel therapeutic opportunity for OSCC by targeting adrenergic nerve fibers, and repurposing nebivolol to treat OSCC can be represented as an effective strategy. Frontiers Media S.A. 2021-08-12 /pmc/articles/PMC8387679/ /pubmed/34456721 http://dx.doi.org/10.3389/fphar.2021.691998 Text en Copyright © 2021 Chen, Jiang, Wang, Cai, Jiang, Xie, Zhou, Zeng, Ji, Shen and Chen. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Chen, Qian
Jiang, Han
Wang, Zhen
Cai, Lu-Yao
Jiang, Yu-Chen
Xie, Liang
Zhou, Yu
Zeng, Xin
Ji, Ning
Shen, Ying-Qiang
Chen, Qian-Ming
Adrenergic Blockade by Nebivolol to Suppress Oral Squamous Cell Carcinoma Growth via Endoplasmic Reticulum Stress and Mitochondria Dysfunction
title Adrenergic Blockade by Nebivolol to Suppress Oral Squamous Cell Carcinoma Growth via Endoplasmic Reticulum Stress and Mitochondria Dysfunction
title_full Adrenergic Blockade by Nebivolol to Suppress Oral Squamous Cell Carcinoma Growth via Endoplasmic Reticulum Stress and Mitochondria Dysfunction
title_fullStr Adrenergic Blockade by Nebivolol to Suppress Oral Squamous Cell Carcinoma Growth via Endoplasmic Reticulum Stress and Mitochondria Dysfunction
title_full_unstemmed Adrenergic Blockade by Nebivolol to Suppress Oral Squamous Cell Carcinoma Growth via Endoplasmic Reticulum Stress and Mitochondria Dysfunction
title_short Adrenergic Blockade by Nebivolol to Suppress Oral Squamous Cell Carcinoma Growth via Endoplasmic Reticulum Stress and Mitochondria Dysfunction
title_sort adrenergic blockade by nebivolol to suppress oral squamous cell carcinoma growth via endoplasmic reticulum stress and mitochondria dysfunction
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387679/
https://www.ncbi.nlm.nih.gov/pubmed/34456721
http://dx.doi.org/10.3389/fphar.2021.691998
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