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Withaferin A triggers G2/M arrest and intrinsic apoptosis in glioblastoma cells via ATF4‐ATF3‐CHOP axis
OBJECTIVE: Withaferin A (WA) is a bioactive compound with a remarkable anti‐cancer effect derived from Withania somnifera, commonly known as ashwagandha. However, the anti‐cancer mechanisms of WA in glioblastoma multiforme (GBM) are still unclear. MATERIALS AND METHODS: Cell viability assays and xen...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985693/ https://www.ncbi.nlm.nih.gov/pubmed/31642559 http://dx.doi.org/10.1111/cpr.12706 |
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author | Tang, Qin Ren, Liwen Liu, Jinyi Li, Wan Zheng, Xiangjin Wang, Jinhua Du, Guanhua |
author_facet | Tang, Qin Ren, Liwen Liu, Jinyi Li, Wan Zheng, Xiangjin Wang, Jinhua Du, Guanhua |
author_sort | Tang, Qin |
collection | PubMed |
description | OBJECTIVE: Withaferin A (WA) is a bioactive compound with a remarkable anti‐cancer effect derived from Withania somnifera, commonly known as ashwagandha. However, the anti‐cancer mechanisms of WA in glioblastoma multiforme (GBM) are still unclear. MATERIALS AND METHODS: Cell viability assays and xenografted nude mice were used to evaluate the effects of WA, along with flow cytometry to detect apoptosis and cell cycle of GBM. RNA‐seq analysis, Western blotting, immunofluorescence staining, qRT‐PCR and siRNA gene silencing were carried out to determine the signalling pathways affected by WA. RESULTS: Withaferin A significantly inhibited the growth of GBM in vitro and in vivo and triggered the intrinsic apoptosis of GBM cells by up‐regulating expression of Bim and Bad. WA arrested GBM cells at the G2/M phase of the cell cycle through dephosphorylating Thr(161) of CDK1 by activating p53‐independent p21 up‐regulation. Knockdown of p21 restored cell cycle progression and cell viability by down‐regulating the expression of Bad rather than Bim. We demonstrated that endoplasmic reticulum (ER) stress induced by WA through the ATF4‐ATF3‐CHOP axis, initiated apoptosis and G2/M arrest in GBM cells. CONCLUSION: We revealed a novel pathway that elucidated WA activation of apoptosis and G2/M arrest in GBM cells through the ATF4‐ATF3‐CHOP axis. This discovery is important for optimization of WA‐based regimens for prevention and/or treatment of GBM. |
format | Online Article Text |
id | pubmed-6985693 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-69856932020-03-13 Withaferin A triggers G2/M arrest and intrinsic apoptosis in glioblastoma cells via ATF4‐ATF3‐CHOP axis Tang, Qin Ren, Liwen Liu, Jinyi Li, Wan Zheng, Xiangjin Wang, Jinhua Du, Guanhua Cell Prolif Original Articles OBJECTIVE: Withaferin A (WA) is a bioactive compound with a remarkable anti‐cancer effect derived from Withania somnifera, commonly known as ashwagandha. However, the anti‐cancer mechanisms of WA in glioblastoma multiforme (GBM) are still unclear. MATERIALS AND METHODS: Cell viability assays and xenografted nude mice were used to evaluate the effects of WA, along with flow cytometry to detect apoptosis and cell cycle of GBM. RNA‐seq analysis, Western blotting, immunofluorescence staining, qRT‐PCR and siRNA gene silencing were carried out to determine the signalling pathways affected by WA. RESULTS: Withaferin A significantly inhibited the growth of GBM in vitro and in vivo and triggered the intrinsic apoptosis of GBM cells by up‐regulating expression of Bim and Bad. WA arrested GBM cells at the G2/M phase of the cell cycle through dephosphorylating Thr(161) of CDK1 by activating p53‐independent p21 up‐regulation. Knockdown of p21 restored cell cycle progression and cell viability by down‐regulating the expression of Bad rather than Bim. We demonstrated that endoplasmic reticulum (ER) stress induced by WA through the ATF4‐ATF3‐CHOP axis, initiated apoptosis and G2/M arrest in GBM cells. CONCLUSION: We revealed a novel pathway that elucidated WA activation of apoptosis and G2/M arrest in GBM cells through the ATF4‐ATF3‐CHOP axis. This discovery is important for optimization of WA‐based regimens for prevention and/or treatment of GBM. John Wiley and Sons Inc. 2019-10-23 /pmc/articles/PMC6985693/ /pubmed/31642559 http://dx.doi.org/10.1111/cpr.12706 Text en © 2019 The Authors. Cell Proliferation Published by John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Tang, Qin Ren, Liwen Liu, Jinyi Li, Wan Zheng, Xiangjin Wang, Jinhua Du, Guanhua Withaferin A triggers G2/M arrest and intrinsic apoptosis in glioblastoma cells via ATF4‐ATF3‐CHOP axis |
title | Withaferin A triggers G2/M arrest and intrinsic apoptosis in glioblastoma cells via ATF4‐ATF3‐CHOP axis |
title_full | Withaferin A triggers G2/M arrest and intrinsic apoptosis in glioblastoma cells via ATF4‐ATF3‐CHOP axis |
title_fullStr | Withaferin A triggers G2/M arrest and intrinsic apoptosis in glioblastoma cells via ATF4‐ATF3‐CHOP axis |
title_full_unstemmed | Withaferin A triggers G2/M arrest and intrinsic apoptosis in glioblastoma cells via ATF4‐ATF3‐CHOP axis |
title_short | Withaferin A triggers G2/M arrest and intrinsic apoptosis in glioblastoma cells via ATF4‐ATF3‐CHOP axis |
title_sort | withaferin a triggers g2/m arrest and intrinsic apoptosis in glioblastoma cells via atf4‐atf3‐chop axis |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985693/ https://www.ncbi.nlm.nih.gov/pubmed/31642559 http://dx.doi.org/10.1111/cpr.12706 |
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