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Oncogenic Ras is downregulated by ARHI and induces autophagy by Ras/AKT/mTOR pathway in glioblastoma
BACKGROUND: Glioblastoma is a disease with high heterogeneity that has long been difficult for doctors to identify and treat. ARHI is a remarkable tumor suppressor gene in human ovarian cancer and many other cancers. We found over-expression of ARHI can also inhibit cancer cell proliferation, decrea...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515631/ https://www.ncbi.nlm.nih.gov/pubmed/31088402 http://dx.doi.org/10.1186/s12885-019-5643-z |
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author | Zhong, Chen Shu, Mengting Ye, Junyi Wang, Xiaoxiong Chen, Xin Liu, Zhendong Zhao, Wenyang Zhao, Boxian Zheng, Zhixing Yin, Zhiqin Gao, Ming Zhao, Haiqi Wang, Kaikai Zhao, Shiguang |
author_facet | Zhong, Chen Shu, Mengting Ye, Junyi Wang, Xiaoxiong Chen, Xin Liu, Zhendong Zhao, Wenyang Zhao, Boxian Zheng, Zhixing Yin, Zhiqin Gao, Ming Zhao, Haiqi Wang, Kaikai Zhao, Shiguang |
author_sort | Zhong, Chen |
collection | PubMed |
description | BACKGROUND: Glioblastoma is a disease with high heterogeneity that has long been difficult for doctors to identify and treat. ARHI is a remarkable tumor suppressor gene in human ovarian cancer and many other cancers. We found over-expression of ARHI can also inhibit cancer cell proliferation, decrease tumorigenicity, and induce autophagic cell death in human glioma and inhibition of the late stage of autophagy can further enhance the antitumor effect of ARHI through inducing apoptosis in vitro or vivo. METHODS: Using MTT assay to detect cell viability. The colony formation assay was used to measure single cell clonogenicity. Autophagy associated morphological changes were tested by transmission electron microscopy. Flow cytometry and TUNEL staining were used to measure the apoptosis rate. Autophagy inhibitor chloroquine (CQ) was used to study the effects of inhibition at late stage of autophagy on ARHI-induced autophagy and apoptosis. Protein expression were detected by Western blot, immunofluorescence and immunohistochemical analyses. LN229-derived xenografts were established to observe the effect of ARHI in vivo. RESULTS: ARHI induced autophagic death in glioma cells, and blocking late-stage autophagy markedly enhanced the antiproliferative activites of ARHI. In our research, we observed the inhibition of RAS-AKT-mTOR signaling in ARHI-glioma cells and blockade of autophagy flux at late stage by CQ enhanced the cytotoxicity of ARHI, caused accumulation of autophagic vacuoles and robust apoptosis. As a result, the inhibition of RAS augmented autophagy of glioma cells. CONCLUSION: ARHI may also be a functional tumor suppressor in glioma. And chloroquine (CQ) used as an auxiliary medicine in glioma chemotherapy can enhance the antitumor effect of ARHI, and this study provides a novel mechanistic basis and strategy for glioma therapy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12885-019-5643-z) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6515631 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-65156312019-05-21 Oncogenic Ras is downregulated by ARHI and induces autophagy by Ras/AKT/mTOR pathway in glioblastoma Zhong, Chen Shu, Mengting Ye, Junyi Wang, Xiaoxiong Chen, Xin Liu, Zhendong Zhao, Wenyang Zhao, Boxian Zheng, Zhixing Yin, Zhiqin Gao, Ming Zhao, Haiqi Wang, Kaikai Zhao, Shiguang BMC Cancer Research Article BACKGROUND: Glioblastoma is a disease with high heterogeneity that has long been difficult for doctors to identify and treat. ARHI is a remarkable tumor suppressor gene in human ovarian cancer and many other cancers. We found over-expression of ARHI can also inhibit cancer cell proliferation, decrease tumorigenicity, and induce autophagic cell death in human glioma and inhibition of the late stage of autophagy can further enhance the antitumor effect of ARHI through inducing apoptosis in vitro or vivo. METHODS: Using MTT assay to detect cell viability. The colony formation assay was used to measure single cell clonogenicity. Autophagy associated morphological changes were tested by transmission electron microscopy. Flow cytometry and TUNEL staining were used to measure the apoptosis rate. Autophagy inhibitor chloroquine (CQ) was used to study the effects of inhibition at late stage of autophagy on ARHI-induced autophagy and apoptosis. Protein expression were detected by Western blot, immunofluorescence and immunohistochemical analyses. LN229-derived xenografts were established to observe the effect of ARHI in vivo. RESULTS: ARHI induced autophagic death in glioma cells, and blocking late-stage autophagy markedly enhanced the antiproliferative activites of ARHI. In our research, we observed the inhibition of RAS-AKT-mTOR signaling in ARHI-glioma cells and blockade of autophagy flux at late stage by CQ enhanced the cytotoxicity of ARHI, caused accumulation of autophagic vacuoles and robust apoptosis. As a result, the inhibition of RAS augmented autophagy of glioma cells. CONCLUSION: ARHI may also be a functional tumor suppressor in glioma. And chloroquine (CQ) used as an auxiliary medicine in glioma chemotherapy can enhance the antitumor effect of ARHI, and this study provides a novel mechanistic basis and strategy for glioma therapy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12885-019-5643-z) contains supplementary material, which is available to authorized users. BioMed Central 2019-05-14 /pmc/articles/PMC6515631/ /pubmed/31088402 http://dx.doi.org/10.1186/s12885-019-5643-z Text en © The Author(s). 2019 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 Article Zhong, Chen Shu, Mengting Ye, Junyi Wang, Xiaoxiong Chen, Xin Liu, Zhendong Zhao, Wenyang Zhao, Boxian Zheng, Zhixing Yin, Zhiqin Gao, Ming Zhao, Haiqi Wang, Kaikai Zhao, Shiguang Oncogenic Ras is downregulated by ARHI and induces autophagy by Ras/AKT/mTOR pathway in glioblastoma |
title | Oncogenic Ras is downregulated by ARHI and induces autophagy by Ras/AKT/mTOR pathway in glioblastoma |
title_full | Oncogenic Ras is downregulated by ARHI and induces autophagy by Ras/AKT/mTOR pathway in glioblastoma |
title_fullStr | Oncogenic Ras is downregulated by ARHI and induces autophagy by Ras/AKT/mTOR pathway in glioblastoma |
title_full_unstemmed | Oncogenic Ras is downregulated by ARHI and induces autophagy by Ras/AKT/mTOR pathway in glioblastoma |
title_short | Oncogenic Ras is downregulated by ARHI and induces autophagy by Ras/AKT/mTOR pathway in glioblastoma |
title_sort | oncogenic ras is downregulated by arhi and induces autophagy by ras/akt/mtor pathway in glioblastoma |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515631/ https://www.ncbi.nlm.nih.gov/pubmed/31088402 http://dx.doi.org/10.1186/s12885-019-5643-z |
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