Cargando…

Paclitaxel Induces the Apoptosis of Prostate Cancer Cells via ROS-Mediated HIF-1α Expression

Prostate cancer (PCa) is the most common malignancy to endanger the health of male genitourinary system. Clinically, paclitaxel (PTX) (C47H51NO14), a diterpene alkaloid, is commonly used as an effective natural antineoplastic drug during the treatment of PCa. However, the mechanism and pathway invol...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhang, Yan, Tang, Yedong, Tang, Xiaoqiong, Wang, Yuhua, Zhang, Zhenghong, Yang, Hongqin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9654100/
https://www.ncbi.nlm.nih.gov/pubmed/36364008
http://dx.doi.org/10.3390/molecules27217183
_version_ 1784828845719814144
author Zhang, Yan
Tang, Yedong
Tang, Xiaoqiong
Wang, Yuhua
Zhang, Zhenghong
Yang, Hongqin
author_facet Zhang, Yan
Tang, Yedong
Tang, Xiaoqiong
Wang, Yuhua
Zhang, Zhenghong
Yang, Hongqin
author_sort Zhang, Yan
collection PubMed
description Prostate cancer (PCa) is the most common malignancy to endanger the health of male genitourinary system. Clinically, paclitaxel (PTX) (C47H51NO14), a diterpene alkaloid, is commonly used as an effective natural antineoplastic drug during the treatment of PCa. However, the mechanism and pathway involved in the function of PTX are poorly understood. In the current study, we employed the CCK-8 assay, revealing that PTX can inhibit the survival and induce the apoptosis of PC3M cells (a human prostate cancer cell line) in a concentration-dependent manner. Reactive oxygen species (ROS), as a metabolic intermediate produced by the mitochondrial respiratory chain, are highly accumulated under the PTX treatment, which results in a sharp decrease of the mitochondrial membrane potential in PC3M cells. Additionally, the migration and invasion of PC3M cells are weakened due to PTX treatment. Further analysis reveals that N-acetylcysteine (NAC), which functions as an antioxidant, not only rescues the decreased mitochondrial membrane potential induced by the abnormal ROS level, but also restores the migration and invasion of PC3M cells. In a subsequent exploration of the detailed mechanism, we found that hypoxia-inducible factor (HIF)-1α works as a downstream gene that can respond to the increased ROS in PC3M cells. Under PTX treatment, the expression levels of HIF-1α mRNA and protein are significantly increased, which stimulate the activation of JNK/caspase-3 signaling and promote the apoptosis of PC3M cells. In summary, we demonstrate that PTX regulates the expression of HIF-1α through increased ROS accumulation, thereby promoting the activation of JNK/caspase-3 pathway to induce the apoptosis of PCa cells. This study provides new insights into the mechanism of antineoplastic action of taxanes and unveils the clinical benefit of the ROS-HIF-1α signaling pathway, which may offer a potential therapeutic target to prevent the development of PCa.
format Online
Article
Text
id pubmed-9654100
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-96541002022-11-15 Paclitaxel Induces the Apoptosis of Prostate Cancer Cells via ROS-Mediated HIF-1α Expression Zhang, Yan Tang, Yedong Tang, Xiaoqiong Wang, Yuhua Zhang, Zhenghong Yang, Hongqin Molecules Article Prostate cancer (PCa) is the most common malignancy to endanger the health of male genitourinary system. Clinically, paclitaxel (PTX) (C47H51NO14), a diterpene alkaloid, is commonly used as an effective natural antineoplastic drug during the treatment of PCa. However, the mechanism and pathway involved in the function of PTX are poorly understood. In the current study, we employed the CCK-8 assay, revealing that PTX can inhibit the survival and induce the apoptosis of PC3M cells (a human prostate cancer cell line) in a concentration-dependent manner. Reactive oxygen species (ROS), as a metabolic intermediate produced by the mitochondrial respiratory chain, are highly accumulated under the PTX treatment, which results in a sharp decrease of the mitochondrial membrane potential in PC3M cells. Additionally, the migration and invasion of PC3M cells are weakened due to PTX treatment. Further analysis reveals that N-acetylcysteine (NAC), which functions as an antioxidant, not only rescues the decreased mitochondrial membrane potential induced by the abnormal ROS level, but also restores the migration and invasion of PC3M cells. In a subsequent exploration of the detailed mechanism, we found that hypoxia-inducible factor (HIF)-1α works as a downstream gene that can respond to the increased ROS in PC3M cells. Under PTX treatment, the expression levels of HIF-1α mRNA and protein are significantly increased, which stimulate the activation of JNK/caspase-3 signaling and promote the apoptosis of PC3M cells. In summary, we demonstrate that PTX regulates the expression of HIF-1α through increased ROS accumulation, thereby promoting the activation of JNK/caspase-3 pathway to induce the apoptosis of PCa cells. This study provides new insights into the mechanism of antineoplastic action of taxanes and unveils the clinical benefit of the ROS-HIF-1α signaling pathway, which may offer a potential therapeutic target to prevent the development of PCa. MDPI 2022-10-24 /pmc/articles/PMC9654100/ /pubmed/36364008 http://dx.doi.org/10.3390/molecules27217183 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zhang, Yan
Tang, Yedong
Tang, Xiaoqiong
Wang, Yuhua
Zhang, Zhenghong
Yang, Hongqin
Paclitaxel Induces the Apoptosis of Prostate Cancer Cells via ROS-Mediated HIF-1α Expression
title Paclitaxel Induces the Apoptosis of Prostate Cancer Cells via ROS-Mediated HIF-1α Expression
title_full Paclitaxel Induces the Apoptosis of Prostate Cancer Cells via ROS-Mediated HIF-1α Expression
title_fullStr Paclitaxel Induces the Apoptosis of Prostate Cancer Cells via ROS-Mediated HIF-1α Expression
title_full_unstemmed Paclitaxel Induces the Apoptosis of Prostate Cancer Cells via ROS-Mediated HIF-1α Expression
title_short Paclitaxel Induces the Apoptosis of Prostate Cancer Cells via ROS-Mediated HIF-1α Expression
title_sort paclitaxel induces the apoptosis of prostate cancer cells via ros-mediated hif-1α expression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9654100/
https://www.ncbi.nlm.nih.gov/pubmed/36364008
http://dx.doi.org/10.3390/molecules27217183
work_keys_str_mv AT zhangyan paclitaxelinducestheapoptosisofprostatecancercellsviarosmediatedhif1aexpression
AT tangyedong paclitaxelinducestheapoptosisofprostatecancercellsviarosmediatedhif1aexpression
AT tangxiaoqiong paclitaxelinducestheapoptosisofprostatecancercellsviarosmediatedhif1aexpression
AT wangyuhua paclitaxelinducestheapoptosisofprostatecancercellsviarosmediatedhif1aexpression
AT zhangzhenghong paclitaxelinducestheapoptosisofprostatecancercellsviarosmediatedhif1aexpression
AT yanghongqin paclitaxelinducestheapoptosisofprostatecancercellsviarosmediatedhif1aexpression