Oncogenic Ras is downregulated by ARHI and induces autophagy by Ras/AKT/mTOR pathway in glioblastoma
Identifieur interne : 000572 ( Main/Exploration ); précédent : 000571; suivant : 000573Oncogenic Ras is downregulated by ARHI and induces autophagy by Ras/AKT/mTOR pathway in glioblastoma
Auteurs : Chen Zhong ; Mengting Shu ; Junyi Ye ; Xiaoxiong Wang ; Xin Chen ; Zhendong Liu ; Wenyang Zhao ; Boxian Zhao ; Zhixing Zheng ; Zhiqin Yin ; Ming Gao ; Haiqi Zhao ; Kaikai Wang ; Shiguang ZhaoSource :
- BMC Cancer [ 1471-2407 ] ; 2019.
Abstract
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.
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.
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.
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.
The online version of this article (10.1186/s12885-019-5643-z) contains supplementary material, which is available to authorized users.
Url:
DOI: 10.1186/s12885-019-5643-z
PubMed: 31088402
PubMed Central: 6515631
Affiliations:
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Le document en format XML
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<author><name sortKey="Wang, Kaikai" sort="Wang, Kaikai" uniqKey="Wang K" first="Kaikai" last="Wang">Kaikai Wang</name>
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No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
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<author><name sortKey="Zhao, Shiguang" sort="Zhao, Shiguang" uniqKey="Zhao S" first="Shiguang" last="Zhao">Shiguang Zhao</name>
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No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
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</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Oncogenic Ras is downregulated by ARHI and induces autophagy by Ras/AKT/mTOR pathway in glioblastoma</title>
<author><name sortKey="Zhong, Chen" sort="Zhong, Chen" uniqKey="Zhong C" first="Chen" last="Zhong">Chen Zhong</name>
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<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Neurosurgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2204 9268</institution-id>
<institution-id institution-id-type="GRID">grid.410736.7</institution-id>
<institution>Institute of Brain Science,</institution>
<institution>Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2204 9268</institution-id>
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<institution>Institute of Neuroscience, Sino-Russian Medical Research Center,</institution>
<institution>Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2204 9268</institution-id>
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<institution>Department of Pharmacology, The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China,</institution>
<institution>College of Pharmacy of Harbin Medical University,</institution>
</institution-wrap>
No. 157 Baojian Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Shu, Mengting" sort="Shu, Mengting" uniqKey="Shu M" first="Mengting" last="Shu">Mengting Shu</name>
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<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Neurosurgery,</institution>
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</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2204 9268</institution-id>
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<institution>Institute of Brain Science,</institution>
<institution>Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2204 9268</institution-id>
<institution-id institution-id-type="GRID">grid.410736.7</institution-id>
<institution>Institute of Neuroscience, Sino-Russian Medical Research Center,</institution>
<institution>Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Ye, Junyi" sort="Ye, Junyi" uniqKey="Ye J" first="Junyi" last="Ye">Junyi Ye</name>
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</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2204 9268</institution-id>
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<institution>Institute of Brain Science,</institution>
<institution>Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2204 9268</institution-id>
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<institution>Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Wang, Xiaoxiong" sort="Wang, Xiaoxiong" uniqKey="Wang X" first="Xiaoxiong" last="Wang">Xiaoxiong Wang</name>
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<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
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</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
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</affiliation>
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<institution-id institution-id-type="GRID">grid.410736.7</institution-id>
<institution>Institute of Brain Science,</institution>
<institution>Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2204 9268</institution-id>
<institution-id institution-id-type="GRID">grid.410736.7</institution-id>
<institution>Institute of Neuroscience, Sino-Russian Medical Research Center,</institution>
<institution>Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Chen, Xin" sort="Chen, Xin" uniqKey="Chen X" first="Xin" last="Chen">Xin Chen</name>
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<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Neurosurgery,</institution>
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</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2204 9268</institution-id>
<institution-id institution-id-type="GRID">grid.410736.7</institution-id>
<institution>Institute of Brain Science,</institution>
<institution>Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2204 9268</institution-id>
<institution-id institution-id-type="GRID">grid.410736.7</institution-id>
<institution>Institute of Neuroscience, Sino-Russian Medical Research Center,</institution>
<institution>Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Liu, Zhendong" sort="Liu, Zhendong" uniqKey="Liu Z" first="Zhendong" last="Liu">Zhendong Liu</name>
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<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Neurosurgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2204 9268</institution-id>
<institution-id institution-id-type="GRID">grid.410736.7</institution-id>
<institution>Institute of Brain Science,</institution>
<institution>Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2204 9268</institution-id>
<institution-id institution-id-type="GRID">grid.410736.7</institution-id>
<institution>Institute of Neuroscience, Sino-Russian Medical Research Center,</institution>
<institution>Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Zhao, Wenyang" sort="Zhao, Wenyang" uniqKey="Zhao W" first="Wenyang" last="Zhao">Wenyang Zhao</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1797 9737</institution-id>
<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Neurosurgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2204 9268</institution-id>
<institution-id institution-id-type="GRID">grid.410736.7</institution-id>
<institution>Institute of Brain Science,</institution>
<institution>Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2204 9268</institution-id>
<institution-id institution-id-type="GRID">grid.410736.7</institution-id>
<institution>Institute of Neuroscience, Sino-Russian Medical Research Center,</institution>
<institution>Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Zhao, Boxian" sort="Zhao, Boxian" uniqKey="Zhao B" first="Boxian" last="Zhao">Boxian Zhao</name>
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<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
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<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
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<institution>Institute of Brain Science,</institution>
<institution>Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2204 9268</institution-id>
<institution-id institution-id-type="GRID">grid.410736.7</institution-id>
<institution>Institute of Neuroscience, Sino-Russian Medical Research Center,</institution>
<institution>Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Zheng, Zhixing" sort="Zheng, Zhixing" uniqKey="Zheng Z" first="Zhixing" last="Zheng">Zhixing Zheng</name>
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<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
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No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2204 9268</institution-id>
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<institution>Institute of Brain Science,</institution>
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</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2204 9268</institution-id>
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<institution>Institute of Neuroscience, Sino-Russian Medical Research Center,</institution>
<institution>Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Yin, Zhiqin" sort="Yin, Zhiqin" uniqKey="Yin Z" first="Zhiqin" last="Yin">Zhiqin Yin</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1797 9737</institution-id>
<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Neurosurgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2204 9268</institution-id>
<institution-id institution-id-type="GRID">grid.410736.7</institution-id>
<institution>Institute of Brain Science,</institution>
<institution>Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2204 9268</institution-id>
<institution-id institution-id-type="GRID">grid.410736.7</institution-id>
<institution>Institute of Neuroscience, Sino-Russian Medical Research Center,</institution>
<institution>Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Gao, Ming" sort="Gao, Ming" uniqKey="Gao M" first="Ming" last="Gao">Ming Gao</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1797 9737</institution-id>
<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Neurosurgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2204 9268</institution-id>
<institution-id institution-id-type="GRID">grid.410736.7</institution-id>
<institution>Institute of Brain Science,</institution>
<institution>Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2204 9268</institution-id>
<institution-id institution-id-type="GRID">grid.410736.7</institution-id>
<institution>Institute of Neuroscience, Sino-Russian Medical Research Center,</institution>
<institution>Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Zhao, Haiqi" sort="Zhao, Haiqi" uniqKey="Zhao H" first="Haiqi" last="Zhao">Haiqi Zhao</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1797 9737</institution-id>
<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Neurosurgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2204 9268</institution-id>
<institution-id institution-id-type="GRID">grid.410736.7</institution-id>
<institution>Institute of Brain Science,</institution>
<institution>Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2204 9268</institution-id>
<institution-id institution-id-type="GRID">grid.410736.7</institution-id>
<institution>Institute of Neuroscience, Sino-Russian Medical Research Center,</institution>
<institution>Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Wang, Kaikai" sort="Wang, Kaikai" uniqKey="Wang K" first="Kaikai" last="Wang">Kaikai Wang</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1797 9737</institution-id>
<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Neurosurgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2204 9268</institution-id>
<institution-id institution-id-type="GRID">grid.410736.7</institution-id>
<institution>Institute of Brain Science,</institution>
<institution>Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2204 9268</institution-id>
<institution-id institution-id-type="GRID">grid.410736.7</institution-id>
<institution>Institute of Neuroscience, Sino-Russian Medical Research Center,</institution>
<institution>Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Zhao, Shiguang" sort="Zhao, Shiguang" uniqKey="Zhao S" first="Shiguang" last="Zhao">Shiguang Zhao</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1797 9737</institution-id>
<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Neurosurgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2204 9268</institution-id>
<institution-id institution-id-type="GRID">grid.410736.7</institution-id>
<institution>Institute of Brain Science,</institution>
<institution>Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2204 9268</institution-id>
<institution-id institution-id-type="GRID">grid.410736.7</institution-id>
<institution>Institute of Neuroscience, Sino-Russian Medical Research Center,</institution>
<institution>Harbin Medical University,</institution>
</institution-wrap>
No. 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province People’s Republic of China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province People’s Republic of China</wicri:noCountry>
</affiliation>
</author>
</analytic>
<series><title level="j">BMC Cancer</title>
<idno type="eISSN">1471-2407</idno>
<imprint><date when="2019">2019</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
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</teiHeader>
<front><div type="abstract" xml:lang="en"><sec><title>Background</title>
<p id="Par1">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.</p>
</sec>
<sec><title>Methods</title>
<p id="Par2">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.</p>
</sec>
<sec><title>Results</title>
<p id="Par3">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.</p>
</sec>
<sec><title>Conclusion</title>
<p id="Par4">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.</p>
</sec>
<sec><title>Electronic supplementary material</title>
<p>The online version of this article (10.1186/s12885-019-5643-z) contains supplementary material, which is available to authorized users.</p>
</sec>
</div>
</front>
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<tree><noCountry><name sortKey="Chen, Xin" sort="Chen, Xin" uniqKey="Chen X" first="Xin" last="Chen">Xin Chen</name>
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