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The role of autophagy in the cytotoxicity induced by trastuzumab emtansine (T-DM1) in HER2-positive breast cancer cells

Trastuzumab emtansine (T-DM1), an antibody–drug conjugate (ADC) of trastuzumab and cytotoxic agent emtansine (DM1), has been approved for the therapy of metastatic HER2-positive breast cancer after prior treatment of trastuzumab and taxane. The impressive efficacy exhibited by T-DM1 has heightened t...

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Autores principales: Liu, Peipei, Fan, Jiajun, Wang, Ziyu, Zai, Wenjing, Song, Ping, Li, Yongping, Ju, Dianwen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270446/
https://www.ncbi.nlm.nih.gov/pubmed/32495214
http://dx.doi.org/10.1186/s13568-020-01044-0
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author Liu, Peipei
Fan, Jiajun
Wang, Ziyu
Zai, Wenjing
Song, Ping
Li, Yongping
Ju, Dianwen
author_facet Liu, Peipei
Fan, Jiajun
Wang, Ziyu
Zai, Wenjing
Song, Ping
Li, Yongping
Ju, Dianwen
author_sort Liu, Peipei
collection PubMed
description Trastuzumab emtansine (T-DM1), an antibody–drug conjugate (ADC) of trastuzumab and cytotoxic agent emtansine (DM1), has been approved for the therapy of metastatic HER2-positive breast cancer after prior treatment of trastuzumab and taxane. The impressive efficacy exhibited by T-DM1 has heightened the need for more further studies on the underlying mechanisms of T-DM1 cytotoxicity. Previous research suggested that autophagy was crucial for cancer therapy, but the role of autophagy in T-DM1 treatment has not been investigated. Here, we demonstrated for the first time that T-DM1 triggered obvious autophagy in HER2-positive SK-BR-3 and BT-474 breast cancer cells. Blocking autophagy with pharmacological inhibitors chloroquine (CQ) or LY294002 partly reduced T-DM1-induced apoptosis and Caspase-3/7 activation, suggesting that autophagy played an essential role in the cytotoxicity induced by T-DM1 in HER2-positive breast cancer cells. Further investigation demonstrated that Akt/mTOR signaling pathway was involved in T-DM1-induced autophagy in a time-dependent manner. Altogether, our results highlighted the important role of autophagy as a novel mechanism for T-DM1-induced cytotoxicity and elucidated the critical relationships between T-DM1-induced autophagy and apoptosis in human HER2-positive breast cancer cells, which provides novel insight into the underlying anti-tumor mechanism of T-DM1.
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spelling pubmed-72704462020-06-15 The role of autophagy in the cytotoxicity induced by trastuzumab emtansine (T-DM1) in HER2-positive breast cancer cells Liu, Peipei Fan, Jiajun Wang, Ziyu Zai, Wenjing Song, Ping Li, Yongping Ju, Dianwen AMB Express Original Article Trastuzumab emtansine (T-DM1), an antibody–drug conjugate (ADC) of trastuzumab and cytotoxic agent emtansine (DM1), has been approved for the therapy of metastatic HER2-positive breast cancer after prior treatment of trastuzumab and taxane. The impressive efficacy exhibited by T-DM1 has heightened the need for more further studies on the underlying mechanisms of T-DM1 cytotoxicity. Previous research suggested that autophagy was crucial for cancer therapy, but the role of autophagy in T-DM1 treatment has not been investigated. Here, we demonstrated for the first time that T-DM1 triggered obvious autophagy in HER2-positive SK-BR-3 and BT-474 breast cancer cells. Blocking autophagy with pharmacological inhibitors chloroquine (CQ) or LY294002 partly reduced T-DM1-induced apoptosis and Caspase-3/7 activation, suggesting that autophagy played an essential role in the cytotoxicity induced by T-DM1 in HER2-positive breast cancer cells. Further investigation demonstrated that Akt/mTOR signaling pathway was involved in T-DM1-induced autophagy in a time-dependent manner. Altogether, our results highlighted the important role of autophagy as a novel mechanism for T-DM1-induced cytotoxicity and elucidated the critical relationships between T-DM1-induced autophagy and apoptosis in human HER2-positive breast cancer cells, which provides novel insight into the underlying anti-tumor mechanism of T-DM1. Springer Berlin Heidelberg 2020-06-03 /pmc/articles/PMC7270446/ /pubmed/32495214 http://dx.doi.org/10.1186/s13568-020-01044-0 Text en © The Author(s) 2020 Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Original Article
Liu, Peipei
Fan, Jiajun
Wang, Ziyu
Zai, Wenjing
Song, Ping
Li, Yongping
Ju, Dianwen
The role of autophagy in the cytotoxicity induced by trastuzumab emtansine (T-DM1) in HER2-positive breast cancer cells
title The role of autophagy in the cytotoxicity induced by trastuzumab emtansine (T-DM1) in HER2-positive breast cancer cells
title_full The role of autophagy in the cytotoxicity induced by trastuzumab emtansine (T-DM1) in HER2-positive breast cancer cells
title_fullStr The role of autophagy in the cytotoxicity induced by trastuzumab emtansine (T-DM1) in HER2-positive breast cancer cells
title_full_unstemmed The role of autophagy in the cytotoxicity induced by trastuzumab emtansine (T-DM1) in HER2-positive breast cancer cells
title_short The role of autophagy in the cytotoxicity induced by trastuzumab emtansine (T-DM1) in HER2-positive breast cancer cells
title_sort role of autophagy in the cytotoxicity induced by trastuzumab emtansine (t-dm1) in her2-positive breast cancer cells
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270446/
https://www.ncbi.nlm.nih.gov/pubmed/32495214
http://dx.doi.org/10.1186/s13568-020-01044-0
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