Suberoylanilide hydroxamic acid (SAHA) causes tumor growth slowdown and triggers autophagy in glioblastoma stem cells.
Identifieur interne : 001108 ( Main/Exploration ); précédent : 001107; suivant : 001109Suberoylanilide hydroxamic acid (SAHA) causes tumor growth slowdown and triggers autophagy in glioblastoma stem cells.
Auteurs : Ming-Tsang Chiao [Taïwan] ; Wen-Yu Cheng [Taïwan] ; Yi-Chin Yang [Taïwan] ; Chiung-Chyi Shen [Taïwan] ; Jiunn-Liang Ko [Taïwan]Source :
- Autophagy [ 1554-8635 ] ; 2013.
Descripteurs français
- KwdFr :
- Acides hydroxamiques (pharmacologie), Apoptose (), Autophagie (), Cellules souches tumorales (), Cellules souches tumorales (cytologie), Glioblastome (anatomopathologie), Glioblastome (traitement médicamenteux), Humains, Inhibiteurs de désacétylase d'histone (pharmacologie), Lignée cellulaire tumorale, Phagosomes (métabolisme), Transduction du signal ().
- MESH :
- anatomopathologie : Glioblastome.
- cytologie : Cellules souches tumorales.
- métabolisme : Phagosomes.
- pharmacologie : Acides hydroxamiques, Inhibiteurs de désacétylase d'histone.
- traitement médicamenteux : Glioblastome.
- Apoptose, Autophagie, Cellules souches tumorales, Humains, Lignée cellulaire tumorale, Transduction du signal.
English descriptors
- KwdEn :
- Apoptosis (drug effects), Autophagy (drug effects), Cell Line, Tumor, Glioblastoma (drug therapy), Glioblastoma (pathology), Histone Deacetylase Inhibitors (pharmacology), Humans, Hydroxamic Acids (pharmacology), Neoplastic Stem Cells (cytology), Neoplastic Stem Cells (drug effects), Phagosomes (metabolism), Signal Transduction (drug effects), Vorinostat.
- MESH :
- chemical , pharmacology : Histone Deacetylase Inhibitors, Hydroxamic Acids.
- cytology : Neoplastic Stem Cells.
- drug effects : Apoptosis, Autophagy, Neoplastic Stem Cells, Signal Transduction.
- drug therapy : Glioblastoma.
- metabolism : Phagosomes.
- pathology : Glioblastoma.
- Cell Line, Tumor, Humans, Vorinostat.
Abstract
Although suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, has been used in clinical trials for cancer therapies, its pharmacological effects occur through a poorly understood mechanism. Here, we report that SAHA specifically triggers autophagy and reduces cell viability via promotion of apoptosis in the late phase of glioblastoma stem cells (GSCs). Using a cell line cultured from a glioblastoma biopsy, we investigated the properties and effects of GSCs under SAHA treatment in vitro. In vivo xenograft assays revealed that SAHA effectively caused tumor growth slowdown and the induction of autophagy. SAHA was sufficient to increase formation of intracellular acidic vesicle organelles, recruitment of LC3-II to the autophagosomes, potentiation of BECN1 protein levels and reduced SQSTM1 levels. We determined that SAHA triggered autophagy through the downregulation of AKT-MTOR signaling, a major suppressive cascade of autophagy. Interestingly, upon depletion or pharmacological inhibition of autophagy, SAHA facilitates apoptosis and results in cell death at the early phase, suggesting that SAHA-induced autophagy functions probably act as a prosurvival mechanism. Furthermore, our results also indicated that the inhibition of SAHA-induced autophagy using chloroquine has synergistic effects that further increase apoptosis. Moreover, we found that a reduced dose of SAHA functioned as a potent modulator of differentiation and senescence. Taken together, our results provide a new perspective on the treatment of GSCs, indicating that SAHA is a promising agent for targeting GSCs through the induction of autophagy.
DOI: 10.4161/auto.25664
PubMed: 23962875
Affiliations:
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Chung Shan Medical University; Taichung, Taiwan; Institute of Medical and Molecular Toxicology; Chung Shan Medical University; Taichung, Taiwan.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Institute of Medicine; Chung Shan Medical University; Taichung, Taiwan; Institute of Medical and Molecular Toxicology; Chung Shan Medical University; Taichung</wicri:regionArea><wicri:noRegion>Taiwan; Institute of Medical and Molecular Toxicology; Chung Shan Medical University; Taichung</wicri:noRegion></affiliation></author><author><name sortKey="Cheng, Wen Yu" sort="Cheng, Wen Yu" uniqKey="Cheng W" first="Wen-Yu" last="Cheng">Wen-Yu Cheng</name><affiliation wicri:level="1"><nlm:affiliation>Department of Neurosurgery; Taichung Veterans General Hospital; Taichung, Taiwan.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Neurosurgery; Taichung Veterans General Hospital; Taichung</wicri:regionArea></affiliation></author><author><name sortKey="Yang, Yi Chin" sort="Yang, Yi Chin" uniqKey="Yang Y" first="Yi-Chin" last="Yang">Yi-Chin Yang</name><affiliation wicri:level="1"><nlm:affiliation>Department of Neurosurgery; Taichung Veterans General Hospital; Taichung, Taiwan.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Neurosurgery; Taichung Veterans General Hospital; Taichung</wicri:regionArea></affiliation></author><author><name sortKey="Shen, Chiung Chyi" sort="Shen, Chiung Chyi" uniqKey="Shen C" first="Chiung-Chyi" last="Shen">Chiung-Chyi Shen</name><affiliation wicri:level="1"><nlm:affiliation>Department of Neurosurgery; Taichung Veterans General Hospital; Taichung, Taiwan; Department of Medicine; National Defense Medical Center; Taipei, Taiwan; Tri-Service General Hospital; National Defense Medical Center; Taipei, Taiwan; Department of Physical Therapy; Hungkuang University; Taichung, Taiwan.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Neurosurgery; Taichung Veterans General Hospital; Taichung, Taiwan; Department of Medicine; National Defense Medical Center; Taipei, Taiwan; Tri-Service General Hospital; National Defense Medical Center; Taipei, Taiwan; Department of Physical Therapy; Hungkuang University; Taichung</wicri:regionArea><wicri:noRegion>Taiwan; Department of Physical Therapy; Hungkuang University; Taichung</wicri:noRegion></affiliation></author><author><name sortKey="Ko, Jiunn Liang" sort="Ko, Jiunn Liang" uniqKey="Ko J" first="Jiunn-Liang" last="Ko">Jiunn-Liang Ko</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Medicine; Chung Shan Medical University; Taichung, Taiwan; Institute of Medical and Molecular Toxicology; Chung Shan Medical University; Taichung, Taiwan; Department of Medical Oncology; Chung Shan Medical University Hospital; Taichung, Taiwan; Lung Cancer Research Center; Institute of Medicine; Chung Shan Medical University Hospital; Taichung, Taiwan.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Institute of Medicine; Chung Shan Medical University; Taichung, Taiwan; Institute of Medical and Molecular Toxicology; Chung Shan Medical University; Taichung, Taiwan; Department of Medical Oncology; Chung Shan Medical University Hospital; Taichung, Taiwan; Lung Cancer Research Center; Institute of Medicine; Chung Shan Medical University Hospital; Taichung</wicri:regionArea><wicri:noRegion>Taiwan; Lung Cancer Research Center; Institute of Medicine; Chung Shan Medical University Hospital; Taichung</wicri:noRegion></affiliation></author></analytic><series><title level="j">Autophagy</title><idno type="eISSN">1554-8635</idno><imprint><date when="2013" type="published">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Apoptosis (drug effects)</term><term>Autophagy (drug effects)</term><term>Cell Line, Tumor</term><term>Glioblastoma (drug therapy)</term><term>Glioblastoma (pathology)</term><term>Histone Deacetylase Inhibitors (pharmacology)</term><term>Humans</term><term>Hydroxamic Acids (pharmacology)</term><term>Neoplastic Stem Cells (cytology)</term><term>Neoplastic Stem Cells (drug effects)</term><term>Phagosomes (metabolism)</term><term>Signal Transduction (drug effects)</term><term>Vorinostat</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Acides hydroxamiques (pharmacologie)</term><term>Apoptose ()</term><term>Autophagie ()</term><term>Cellules souches tumorales ()</term><term>Cellules souches tumorales (cytologie)</term><term>Glioblastome (anatomopathologie)</term><term>Glioblastome (traitement médicamenteux)</term><term>Humains</term><term>Inhibiteurs de désacétylase d'histone (pharmacologie)</term><term>Lignée cellulaire tumorale</term><term>Phagosomes (métabolisme)</term><term>Transduction du signal ()</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Histone Deacetylase Inhibitors</term><term>Hydroxamic Acids</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Glioblastome</term></keywords><keywords scheme="MESH" qualifier="cytologie" xml:lang="fr"><term>Cellules souches tumorales</term></keywords><keywords scheme="MESH" qualifier="cytology" xml:lang="en"><term>Neoplastic Stem Cells</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Apoptosis</term><term>Autophagy</term><term>Neoplastic Stem Cells</term><term>Signal Transduction</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Glioblastoma</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Phagosomes</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Phagosomes</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Glioblastoma</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Acides hydroxamiques</term><term>Inhibiteurs de désacétylase d'histone</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Glioblastome</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cell Line, Tumor</term><term>Humans</term><term>Vorinostat</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Apoptose</term><term>Autophagie</term><term>Cellules souches tumorales</term><term>Humains</term><term>Lignée cellulaire tumorale</term><term>Transduction du signal</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Although suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, has been used in clinical trials for cancer therapies, its pharmacological effects occur through a poorly understood mechanism. Here, we report that SAHA specifically triggers autophagy and reduces cell viability via promotion of apoptosis in the late phase of glioblastoma stem cells (GSCs). Using a cell line cultured from a glioblastoma biopsy, we investigated the properties and effects of GSCs under SAHA treatment in vitro. In vivo xenograft assays revealed that SAHA effectively caused tumor growth slowdown and the induction of autophagy. SAHA was sufficient to increase formation of intracellular acidic vesicle organelles, recruitment of LC3-II to the autophagosomes, potentiation of BECN1 protein levels and reduced SQSTM1 levels. We determined that SAHA triggered autophagy through the downregulation of AKT-MTOR signaling, a major suppressive cascade of autophagy. Interestingly, upon depletion or pharmacological inhibition of autophagy, SAHA facilitates apoptosis and results in cell death at the early phase, suggesting that SAHA-induced autophagy functions probably act as a prosurvival mechanism. Furthermore, our results also indicated that the inhibition of SAHA-induced autophagy using chloroquine has synergistic effects that further increase apoptosis. Moreover, we found that a reduced dose of SAHA functioned as a potent modulator of differentiation and senescence. Taken together, our results provide a new perspective on the treatment of GSCs, indicating that SAHA is a promising agent for targeting GSCs through the induction of autophagy. </div></front></TEI><affiliations><list><country><li>Taïwan</li></country></list><tree><country name="Taïwan"><noRegion><name sortKey="Chiao, Ming Tsang" sort="Chiao, Ming Tsang" uniqKey="Chiao M" first="Ming-Tsang" last="Chiao">Ming-Tsang Chiao</name></noRegion><name sortKey="Cheng, Wen Yu" sort="Cheng, Wen Yu" uniqKey="Cheng W" first="Wen-Yu" last="Cheng">Wen-Yu Cheng</name><name sortKey="Ko, Jiunn Liang" sort="Ko, Jiunn Liang" uniqKey="Ko J" first="Jiunn-Liang" last="Ko">Jiunn-Liang Ko</name><name sortKey="Shen, Chiung Chyi" sort="Shen, Chiung Chyi" uniqKey="Shen C" first="Chiung-Chyi" last="Shen">Chiung-Chyi Shen</name><name sortKey="Yang, Yi Chin" sort="Yang, Yi Chin" uniqKey="Yang Y" first="Yi-Chin" last="Yang">Yi-Chin Yang</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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