Cargando…
Severe cellular stress activates apoptosis independently of p53 in osteosarcoma
Apoptosis induced by doxorubicin, bortezomib, or paclitaxel, targeting DNA, 26S proteasome, and microtubules respectively, was assessed in two osteosarcoma cells, p53 wild-type U2OS and p53-null MG63 cells. Doxorubicin-induced apoptosis only occurred in U2OS, not in MG63. In contrast, bortezomib and...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490387/ https://www.ncbi.nlm.nih.gov/pubmed/34608124 http://dx.doi.org/10.1038/s41420-021-00658-y |
_version_ | 1784578512271704064 |
---|---|
author | Ho, Cheng-Jung Ko, Huey-Jiun Liao, Tzu-Shao Zheng, Xiang-Ren Chou, Po-Hsu Wang, Li-Ting Lin, Ru-Wei Chen, Chung-Hwan Wang, Chihuei |
author_facet | Ho, Cheng-Jung Ko, Huey-Jiun Liao, Tzu-Shao Zheng, Xiang-Ren Chou, Po-Hsu Wang, Li-Ting Lin, Ru-Wei Chen, Chung-Hwan Wang, Chihuei |
author_sort | Ho, Cheng-Jung |
collection | PubMed |
description | Apoptosis induced by doxorubicin, bortezomib, or paclitaxel, targeting DNA, 26S proteasome, and microtubules respectively, was assessed in two osteosarcoma cells, p53 wild-type U2OS and p53-null MG63 cells. Doxorubicin-induced apoptosis only occurred in U2OS, not in MG63. In contrast, bortezomib and paclitaxel could drive U2OS or MG63 toward apoptosis effectively, suggesting that apoptosis induced by bortezomib or paclitaxel is p53-independent. The expressions of Bcl2 family members such as Bcl2, Bcl-xl, and Puma could be seen in U2OS and MG63 cells with or without doxorubicin, bortezomib, or paclitaxel treatment. In contrast, another member, Bim, only could be observed in U2OS, not in MG63, under the same conditions. Bim knockdown did not affect the doxorubicin-induced apoptosis in U2OS, suggested that a BH3-only protein other than Bim might participate in apoptosis induced by doxorubicin. Using a BH3-mimetic, ABT-263, to inhibit Bcl2 or Bcl-xl produced a limited apoptotic response in U2OS and MG63 cells, suggesting that this BH3-mimetic cannot activate the Bax/Bak pathway efficiently. Significantly, ABT-263 enhanced doxorubicin- and bortezomib-induced apoptosis synergistically in U2OS and MG63 cells. These results implied that the severe cellular stress caused by doxorubicin or bortezomib might be mediated through a dual process to control apoptosis. Respectively, doxorubicin or bortezomib activates a BH3-only protein in one way and corresponding unknown factors in another way to affect mitochondrial outer membrane permeability, resulting in apoptosis. The combination of doxorubicin with ABT-263 could produce synergistic apoptosis in MG63 cells, which lack p53, suggesting that p53 has no role in doxorubicin-induced apoptosis in osteosarcoma. In addition, ABT-263 enhanced paclitaxel to induce moderate levels of apoptosis. |
format | Online Article Text |
id | pubmed-8490387 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-84903872021-10-07 Severe cellular stress activates apoptosis independently of p53 in osteosarcoma Ho, Cheng-Jung Ko, Huey-Jiun Liao, Tzu-Shao Zheng, Xiang-Ren Chou, Po-Hsu Wang, Li-Ting Lin, Ru-Wei Chen, Chung-Hwan Wang, Chihuei Cell Death Discov Article Apoptosis induced by doxorubicin, bortezomib, or paclitaxel, targeting DNA, 26S proteasome, and microtubules respectively, was assessed in two osteosarcoma cells, p53 wild-type U2OS and p53-null MG63 cells. Doxorubicin-induced apoptosis only occurred in U2OS, not in MG63. In contrast, bortezomib and paclitaxel could drive U2OS or MG63 toward apoptosis effectively, suggesting that apoptosis induced by bortezomib or paclitaxel is p53-independent. The expressions of Bcl2 family members such as Bcl2, Bcl-xl, and Puma could be seen in U2OS and MG63 cells with or without doxorubicin, bortezomib, or paclitaxel treatment. In contrast, another member, Bim, only could be observed in U2OS, not in MG63, under the same conditions. Bim knockdown did not affect the doxorubicin-induced apoptosis in U2OS, suggested that a BH3-only protein other than Bim might participate in apoptosis induced by doxorubicin. Using a BH3-mimetic, ABT-263, to inhibit Bcl2 or Bcl-xl produced a limited apoptotic response in U2OS and MG63 cells, suggesting that this BH3-mimetic cannot activate the Bax/Bak pathway efficiently. Significantly, ABT-263 enhanced doxorubicin- and bortezomib-induced apoptosis synergistically in U2OS and MG63 cells. These results implied that the severe cellular stress caused by doxorubicin or bortezomib might be mediated through a dual process to control apoptosis. Respectively, doxorubicin or bortezomib activates a BH3-only protein in one way and corresponding unknown factors in another way to affect mitochondrial outer membrane permeability, resulting in apoptosis. The combination of doxorubicin with ABT-263 could produce synergistic apoptosis in MG63 cells, which lack p53, suggesting that p53 has no role in doxorubicin-induced apoptosis in osteosarcoma. In addition, ABT-263 enhanced paclitaxel to induce moderate levels of apoptosis. Nature Publishing Group UK 2021-10-04 /pmc/articles/PMC8490387/ /pubmed/34608124 http://dx.doi.org/10.1038/s41420-021-00658-y Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Ho, Cheng-Jung Ko, Huey-Jiun Liao, Tzu-Shao Zheng, Xiang-Ren Chou, Po-Hsu Wang, Li-Ting Lin, Ru-Wei Chen, Chung-Hwan Wang, Chihuei Severe cellular stress activates apoptosis independently of p53 in osteosarcoma |
title | Severe cellular stress activates apoptosis independently of p53 in osteosarcoma |
title_full | Severe cellular stress activates apoptosis independently of p53 in osteosarcoma |
title_fullStr | Severe cellular stress activates apoptosis independently of p53 in osteosarcoma |
title_full_unstemmed | Severe cellular stress activates apoptosis independently of p53 in osteosarcoma |
title_short | Severe cellular stress activates apoptosis independently of p53 in osteosarcoma |
title_sort | severe cellular stress activates apoptosis independently of p53 in osteosarcoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490387/ https://www.ncbi.nlm.nih.gov/pubmed/34608124 http://dx.doi.org/10.1038/s41420-021-00658-y |
work_keys_str_mv | AT hochengjung severecellularstressactivatesapoptosisindependentlyofp53inosteosarcoma AT kohueyjiun severecellularstressactivatesapoptosisindependentlyofp53inosteosarcoma AT liaotzushao severecellularstressactivatesapoptosisindependentlyofp53inosteosarcoma AT zhengxiangren severecellularstressactivatesapoptosisindependentlyofp53inosteosarcoma AT choupohsu severecellularstressactivatesapoptosisindependentlyofp53inosteosarcoma AT wangliting severecellularstressactivatesapoptosisindependentlyofp53inosteosarcoma AT linruwei severecellularstressactivatesapoptosisindependentlyofp53inosteosarcoma AT chenchunghwan severecellularstressactivatesapoptosisindependentlyofp53inosteosarcoma AT wangchihuei severecellularstressactivatesapoptosisindependentlyofp53inosteosarcoma |