Cargando…

Temozolomide-Perillyl alcohol conjugate impairs Mitophagy flux by inducing lysosomal dysfunction in non-small cell lung Cancer cells and sensitizes them to irradiation

BACKGROUND: Temozolomide-perillyl alcohol conjugate (TMZ-POH), a novel Temozolomide (TMZ) analog developed based on the conjugation of TMZ and perillyl alcohol (POH), displayed strong anticancer potency in multiple cancer types. In this study, we aimed to clarify the relationship between TMZ-POH and...

Descripción completa

Detalles Bibliográficos
Autores principales: Chang, Minghui, Song, Xingguo, Geng, Xinran, Wang, Xingwu, Wang, Weijun, Chen, Thomas C., Xie, Li, Song, Xianrang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191917/
https://www.ncbi.nlm.nih.gov/pubmed/30326943
http://dx.doi.org/10.1186/s13046-018-0905-1
_version_ 1783363807022678016
author Chang, Minghui
Song, Xingguo
Geng, Xinran
Wang, Xingwu
Wang, Weijun
Chen, Thomas C.
Xie, Li
Song, Xianrang
author_facet Chang, Minghui
Song, Xingguo
Geng, Xinran
Wang, Xingwu
Wang, Weijun
Chen, Thomas C.
Xie, Li
Song, Xianrang
author_sort Chang, Minghui
collection PubMed
description BACKGROUND: Temozolomide-perillyl alcohol conjugate (TMZ-POH), a novel Temozolomide (TMZ) analog developed based on the conjugation of TMZ and perillyl alcohol (POH), displayed strong anticancer potency in multiple cancer types. In this study, we aimed to clarify the relationship between TMZ-POH and autophagy, and explore the underlying mechanisms involved in. METHODS: The proteins involved in autophagy, mitochondrial fission, lysosomal function and membrane traffic were detected by western blots; Autophagosome, mitochondria and lysosome were visualized by transmission electron microscope (TEM) and immunostaining; Apoptosis analysis and fluorescence probe detection were applied by flow cytometry. RESULTS: TMZ-POH blocked mitophagy flux although the number of autophagosomes which colocalized with mitochondria in the cells was increased via inducing lysosomal dysfunction as evidence from impaired lysosomal acidification, maturation and hampered autophagosome- lysosome fusion, which largely depended on its downregulation on the small GTPase RAB7A via mevalonate pathway. More importantly, our data demonstrated TMZ-POH sensitized cancer cell to irradiation induced apoptosis. CONCLUSIONS: Temozolomide-perillyl alcohol conjugate impairs mitophagy flux by inducing lysosomal dysfunction in Non-Small Cell Lung Cancer (NSCLC) cells and sensitizes them to irradiation, thereby proposing TMZ-POH as a potential radiosensitizer. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13046-018-0905-1) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-6191917
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-61919172018-10-23 Temozolomide-Perillyl alcohol conjugate impairs Mitophagy flux by inducing lysosomal dysfunction in non-small cell lung Cancer cells and sensitizes them to irradiation Chang, Minghui Song, Xingguo Geng, Xinran Wang, Xingwu Wang, Weijun Chen, Thomas C. Xie, Li Song, Xianrang J Exp Clin Cancer Res Research BACKGROUND: Temozolomide-perillyl alcohol conjugate (TMZ-POH), a novel Temozolomide (TMZ) analog developed based on the conjugation of TMZ and perillyl alcohol (POH), displayed strong anticancer potency in multiple cancer types. In this study, we aimed to clarify the relationship between TMZ-POH and autophagy, and explore the underlying mechanisms involved in. METHODS: The proteins involved in autophagy, mitochondrial fission, lysosomal function and membrane traffic were detected by western blots; Autophagosome, mitochondria and lysosome were visualized by transmission electron microscope (TEM) and immunostaining; Apoptosis analysis and fluorescence probe detection were applied by flow cytometry. RESULTS: TMZ-POH blocked mitophagy flux although the number of autophagosomes which colocalized with mitochondria in the cells was increased via inducing lysosomal dysfunction as evidence from impaired lysosomal acidification, maturation and hampered autophagosome- lysosome fusion, which largely depended on its downregulation on the small GTPase RAB7A via mevalonate pathway. More importantly, our data demonstrated TMZ-POH sensitized cancer cell to irradiation induced apoptosis. CONCLUSIONS: Temozolomide-perillyl alcohol conjugate impairs mitophagy flux by inducing lysosomal dysfunction in Non-Small Cell Lung Cancer (NSCLC) cells and sensitizes them to irradiation, thereby proposing TMZ-POH as a potential radiosensitizer. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13046-018-0905-1) contains supplementary material, which is available to authorized users. BioMed Central 2018-10-16 /pmc/articles/PMC6191917/ /pubmed/30326943 http://dx.doi.org/10.1186/s13046-018-0905-1 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 Research
Chang, Minghui
Song, Xingguo
Geng, Xinran
Wang, Xingwu
Wang, Weijun
Chen, Thomas C.
Xie, Li
Song, Xianrang
Temozolomide-Perillyl alcohol conjugate impairs Mitophagy flux by inducing lysosomal dysfunction in non-small cell lung Cancer cells and sensitizes them to irradiation
title Temozolomide-Perillyl alcohol conjugate impairs Mitophagy flux by inducing lysosomal dysfunction in non-small cell lung Cancer cells and sensitizes them to irradiation
title_full Temozolomide-Perillyl alcohol conjugate impairs Mitophagy flux by inducing lysosomal dysfunction in non-small cell lung Cancer cells and sensitizes them to irradiation
title_fullStr Temozolomide-Perillyl alcohol conjugate impairs Mitophagy flux by inducing lysosomal dysfunction in non-small cell lung Cancer cells and sensitizes them to irradiation
title_full_unstemmed Temozolomide-Perillyl alcohol conjugate impairs Mitophagy flux by inducing lysosomal dysfunction in non-small cell lung Cancer cells and sensitizes them to irradiation
title_short Temozolomide-Perillyl alcohol conjugate impairs Mitophagy flux by inducing lysosomal dysfunction in non-small cell lung Cancer cells and sensitizes them to irradiation
title_sort temozolomide-perillyl alcohol conjugate impairs mitophagy flux by inducing lysosomal dysfunction in non-small cell lung cancer cells and sensitizes them to irradiation
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191917/
https://www.ncbi.nlm.nih.gov/pubmed/30326943
http://dx.doi.org/10.1186/s13046-018-0905-1
work_keys_str_mv AT changminghui temozolomideperillylalcoholconjugateimpairsmitophagyfluxbyinducinglysosomaldysfunctioninnonsmallcelllungcancercellsandsensitizesthemtoirradiation
AT songxingguo temozolomideperillylalcoholconjugateimpairsmitophagyfluxbyinducinglysosomaldysfunctioninnonsmallcelllungcancercellsandsensitizesthemtoirradiation
AT gengxinran temozolomideperillylalcoholconjugateimpairsmitophagyfluxbyinducinglysosomaldysfunctioninnonsmallcelllungcancercellsandsensitizesthemtoirradiation
AT wangxingwu temozolomideperillylalcoholconjugateimpairsmitophagyfluxbyinducinglysosomaldysfunctioninnonsmallcelllungcancercellsandsensitizesthemtoirradiation
AT wangweijun temozolomideperillylalcoholconjugateimpairsmitophagyfluxbyinducinglysosomaldysfunctioninnonsmallcelllungcancercellsandsensitizesthemtoirradiation
AT chenthomasc temozolomideperillylalcoholconjugateimpairsmitophagyfluxbyinducinglysosomaldysfunctioninnonsmallcelllungcancercellsandsensitizesthemtoirradiation
AT xieli temozolomideperillylalcoholconjugateimpairsmitophagyfluxbyinducinglysosomaldysfunctioninnonsmallcelllungcancercellsandsensitizesthemtoirradiation
AT songxianrang temozolomideperillylalcoholconjugateimpairsmitophagyfluxbyinducinglysosomaldysfunctioninnonsmallcelllungcancercellsandsensitizesthemtoirradiation