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Excessive mitochondrial fragmentation triggered by erlotinib promotes pancreatic cancer PANC-1 cell apoptosis via activating the mROS-HtrA2/Omi pathways

BACKGROUND: Mitochondrial fragmentation drastically regulates the viability of pancreatic cancer through a poorly understood mechanism. The present study used erlotinib to activate mitochondrial fragmentation and then investigated the downstream events that occurred in response to mitochondrial frag...

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Autores principales: Wan, Jun, Cui, Jie, Wang, Lei, Wu, Kunpeng, Hong, Xiaoping, Zou, Yulin, Zhao, Shuang, Ke, Hong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196464/
https://www.ncbi.nlm.nih.gov/pubmed/30377412
http://dx.doi.org/10.1186/s12935-018-0665-1
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author Wan, Jun
Cui, Jie
Wang, Lei
Wu, Kunpeng
Hong, Xiaoping
Zou, Yulin
Zhao, Shuang
Ke, Hong
author_facet Wan, Jun
Cui, Jie
Wang, Lei
Wu, Kunpeng
Hong, Xiaoping
Zou, Yulin
Zhao, Shuang
Ke, Hong
author_sort Wan, Jun
collection PubMed
description BACKGROUND: Mitochondrial fragmentation drastically regulates the viability of pancreatic cancer through a poorly understood mechanism. The present study used erlotinib to activate mitochondrial fragmentation and then investigated the downstream events that occurred in response to mitochondrial fragmentation. METHODS: Cell viability and apoptosis were determined via MTT assay, TUNEL staining and ELISA. Mitochondrial fragmentation was measured via an immunofluorescence assay and qPCR. siRNA transfection and pathway blockers were used to perform the loss-of-function assays. RESULTS: The results of our study demonstrated that erlotinib treatment mediated cell apoptosis in the PANC-1 pancreatic cancer cell line via evoking mitochondrial fragmentation. Mechanistically, erlotinib application increased mitochondrial fission and reduced mitochondrial fusion, triggering mitochondrial fragmentation. Subsequently, mitochondrial fragmentation caused the overproduction of mitochondrial ROS (mROS). Interestingly, excessive mROS induced cardiolipin oxidation and mPTP opening, finally facilitating HtrA2/Omi liberation from the mitochondria into the cytoplasm, where HtrA2/Omi activated caspase-9-dependent cell apoptosis. Notably, neutralization of mROS or knockdown of HtrA2/Omi attenuated erlotinib-mediated mitochondrial fragmentation and favored cancer cell survival. CONCLUSIONS: Together, our results identified the mROS-HtrA2/Omi axis as a novel signaling pathway that is activated by mitochondrial fragmentation and that promotes PANC-1 pancreatic cancer cell mitochondrial apoptosis in the presence of erlotinib. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12935-018-0665-1) contains supplementary material, which is available to authorized users.
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spelling pubmed-61964642018-10-30 Excessive mitochondrial fragmentation triggered by erlotinib promotes pancreatic cancer PANC-1 cell apoptosis via activating the mROS-HtrA2/Omi pathways Wan, Jun Cui, Jie Wang, Lei Wu, Kunpeng Hong, Xiaoping Zou, Yulin Zhao, Shuang Ke, Hong Cancer Cell Int Primary Research BACKGROUND: Mitochondrial fragmentation drastically regulates the viability of pancreatic cancer through a poorly understood mechanism. The present study used erlotinib to activate mitochondrial fragmentation and then investigated the downstream events that occurred in response to mitochondrial fragmentation. METHODS: Cell viability and apoptosis were determined via MTT assay, TUNEL staining and ELISA. Mitochondrial fragmentation was measured via an immunofluorescence assay and qPCR. siRNA transfection and pathway blockers were used to perform the loss-of-function assays. RESULTS: The results of our study demonstrated that erlotinib treatment mediated cell apoptosis in the PANC-1 pancreatic cancer cell line via evoking mitochondrial fragmentation. Mechanistically, erlotinib application increased mitochondrial fission and reduced mitochondrial fusion, triggering mitochondrial fragmentation. Subsequently, mitochondrial fragmentation caused the overproduction of mitochondrial ROS (mROS). Interestingly, excessive mROS induced cardiolipin oxidation and mPTP opening, finally facilitating HtrA2/Omi liberation from the mitochondria into the cytoplasm, where HtrA2/Omi activated caspase-9-dependent cell apoptosis. Notably, neutralization of mROS or knockdown of HtrA2/Omi attenuated erlotinib-mediated mitochondrial fragmentation and favored cancer cell survival. CONCLUSIONS: Together, our results identified the mROS-HtrA2/Omi axis as a novel signaling pathway that is activated by mitochondrial fragmentation and that promotes PANC-1 pancreatic cancer cell mitochondrial apoptosis in the presence of erlotinib. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12935-018-0665-1) contains supplementary material, which is available to authorized users. BioMed Central 2018-10-22 /pmc/articles/PMC6196464/ /pubmed/30377412 http://dx.doi.org/10.1186/s12935-018-0665-1 Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Primary Research
Wan, Jun
Cui, Jie
Wang, Lei
Wu, Kunpeng
Hong, Xiaoping
Zou, Yulin
Zhao, Shuang
Ke, Hong
Excessive mitochondrial fragmentation triggered by erlotinib promotes pancreatic cancer PANC-1 cell apoptosis via activating the mROS-HtrA2/Omi pathways
title Excessive mitochondrial fragmentation triggered by erlotinib promotes pancreatic cancer PANC-1 cell apoptosis via activating the mROS-HtrA2/Omi pathways
title_full Excessive mitochondrial fragmentation triggered by erlotinib promotes pancreatic cancer PANC-1 cell apoptosis via activating the mROS-HtrA2/Omi pathways
title_fullStr Excessive mitochondrial fragmentation triggered by erlotinib promotes pancreatic cancer PANC-1 cell apoptosis via activating the mROS-HtrA2/Omi pathways
title_full_unstemmed Excessive mitochondrial fragmentation triggered by erlotinib promotes pancreatic cancer PANC-1 cell apoptosis via activating the mROS-HtrA2/Omi pathways
title_short Excessive mitochondrial fragmentation triggered by erlotinib promotes pancreatic cancer PANC-1 cell apoptosis via activating the mROS-HtrA2/Omi pathways
title_sort excessive mitochondrial fragmentation triggered by erlotinib promotes pancreatic cancer panc-1 cell apoptosis via activating the mros-htra2/omi pathways
topic Primary Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196464/
https://www.ncbi.nlm.nih.gov/pubmed/30377412
http://dx.doi.org/10.1186/s12935-018-0665-1
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