3'-epi-12β-hydroxyfroside, a new cardenolide, induces cytoprotective autophagy via blocking the Hsp90/Akt/mTOR axis in lung cancer cells.
Identifieur interne : 000C59 ( Main/Exploration ); précédent : 000C58; suivant : 000C603'-epi-12β-hydroxyfroside, a new cardenolide, induces cytoprotective autophagy via blocking the Hsp90/Akt/mTOR axis in lung cancer cells.
Auteurs : Yan Sun [République populaire de Chine] ; Yong-Hao Huang [République populaire de Chine] ; Feng-Ying Huang [République populaire de Chine] ; Wen-Li Mei [République populaire de Chine] ; Quan Liu [République populaire de Chine] ; Cai-Chun Wang [République populaire de Chine] ; Ying-Ying Lin [République populaire de Chine] ; Canhua Huang [République populaire de Chine] ; Yue-Nan Li [République populaire de Chine] ; Hao-Fu Dai [République populaire de Chine] ; Guang-Hong Tan [République populaire de Chine]Source :
- Theranostics [ 1838-7640 ] ; 2018.
Descripteurs français
- KwdFr :
- Analyse de profil d'expression de gènes, Animaux, Antinéoplasiques (administration et posologie), Antinéoplasiques (pharmacologie), Autophagie (), Cardénolides (administration et posologie), Cardénolides (pharmacologie), Coloration et marquage, Cytométrie en flux, Formazanes (analyse), Humains, Lignée cellulaire tumorale, Microscopie électronique à transmission, Modèles animaux de maladie humaine, Prolifération cellulaire (), Protéine oncogène v-akt (métabolisme), Protéines du choc thermique HSP90 (métabolisme), RT-PCR, Réaction de polymérisation en chaine en temps réel, Résultat thérapeutique, Sels de tétrazolium (analyse), Souris de lignée BALB C, Souris nude, Survie cellulaire (), Sérine-thréonine kinases TOR (métabolisme), Technique d'immunofluorescence, Technique de Western, Transduction du signal (), Transplantation tumorale, Tumeurs du poumon (traitement médicamenteux).
- MESH :
- administration et posologie : Antinéoplasiques, Cardénolides.
- analyse : Formazanes, Sels de tétrazolium.
- métabolisme : Protéine oncogène v-akt, Protéines du choc thermique HSP90, Sérine-thréonine kinases TOR.
- pharmacologie : Antinéoplasiques, Cardénolides.
- traitement médicamenteux : Tumeurs du poumon.
- Analyse de profil d'expression de gènes, Animaux, Autophagie, Coloration et marquage, Cytométrie en flux, Humains, Lignée cellulaire tumorale, Microscopie électronique à transmission, Modèles animaux de maladie humaine, Prolifération cellulaire, RT-PCR, Réaction de polymérisation en chaine en temps réel, Résultat thérapeutique, Souris de lignée BALB C, Souris nude, Survie cellulaire, Technique d'immunofluorescence, Technique de Western, Transduction du signal, Transplantation tumorale.
English descriptors
- KwdEn :
- Animals, Antineoplastic Agents (administration & dosage), Antineoplastic Agents (pharmacology), Autophagy (drug effects), Blotting, Western, Cardenolides (administration & dosage), Cardenolides (pharmacology), Cell Line, Tumor, Cell Proliferation (drug effects), Cell Survival (drug effects), Disease Models, Animal, Flow Cytometry, Fluorescent Antibody Technique, Formazans (analysis), Gene Expression Profiling, HSP90 Heat-Shock Proteins (metabolism), Humans, Lung Neoplasms (drug therapy), Mice, Inbred BALB C, Mice, Nude, Microscopy, Electron, Transmission, Neoplasm Transplantation, Oncogene Protein v-akt (metabolism), Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction (drug effects), Staining and Labeling, TOR Serine-Threonine Kinases (metabolism), Tetrazolium Salts (analysis), Treatment Outcome.
- MESH :
- chemical , administration & dosage : Antineoplastic Agents, Cardenolides.
- chemical , analysis : Formazans, Tetrazolium Salts.
- chemical , metabolism : HSP90 Heat-Shock Proteins, Oncogene Protein v-akt, TOR Serine-Threonine Kinases.
- chemical , pharmacology : Antineoplastic Agents, Cardenolides.
- drug effects : Autophagy, Cell Proliferation, Cell Survival, Signal Transduction.
- drug therapy : Lung Neoplasms.
- Animals, Blotting, Western, Cell Line, Tumor, Disease Models, Animal, Flow Cytometry, Fluorescent Antibody Technique, Gene Expression Profiling, Humans, Mice, Inbred BALB C, Mice, Nude, Microscopy, Electron, Transmission, Neoplasm Transplantation, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Staining and Labeling, Treatment Outcome.
Abstract
Rationale: Cardenolides have potential as anticancer drugs. 3'-epi-12β-hydroxyfroside (HyFS) is a new cardenolide structure isolated by our research group, but its molecular mechanisms remain poorly understood. This study investigates the relationship between its antitumor activities and autophagy in lung cancer cells. Methods: Cell growth and proliferation were detected by MTT, lactate dehydrogenase (LDH) release, 5-ethynyl-20-deoxyuridine (EDU) and colony formation assays. Cell apoptosis was detected by flow cytometry. Autophagic and signal proteins were detected by Western blotting. Markers of autophagy and autophagy flux were also detected by immunofluorescence, transmission electron microscopy and acridine orange staining. Real time RT-PCR was used to analyze the gene expression of Hsp90. Hsp90 ubiquitination was detected by coimmunoprecipitation. The antitumore activities of HyFS were observed in nude mice. Results: HyFS treatment inhibited cell proliferation and induced autophagy in A549 and H460 lung cancer cells, but stronger inhibition of cell proliferation and induction of cell apoptosis were shown when HyFS-mediated autophagy was blocked. The Hsp90/Akt/mTOR axis was found to be involved in the activation of HyFS-mediated autophagy. Evidence of direct interaction between Hsp90 and Akt was observed. HyFS treatment resulted in decreased levels of heat shock protein 90 (Hsp90) and phosphorylated Akt, overexpression of Hsp90 increased activation of autophagy, and inhibition of Hsp90 expression decreased autophagy. In addition, ubiquitin-mediated degradation of Hsp90 and subsequent dephosphorylation of its client protein Akt were also found in HyFS-treated lung cancer cells. Moreover, combination treatment with HyFS and chloroquine showed remarkably increased tumor inhibition in both A549- and H460-bearing mice. Conclusion: Our results demonstrate that HyFS induced cytoprotective autophagy through ubiquitin-mediated degradation of Hsp90, which further blocked the Akt/mTOR pathway in lung cancer cells. Thus, a combination of a HyFS-like cardenolide and an autophagic inhibitor is a potential alternative approach for the treatment of lung cancer.
DOI: 10.7150/thno.23304
PubMed: 29556372
Affiliations:
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Le document en format XML
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<author><name sortKey="Huang, Canhua" sort="Huang, Canhua" uniqKey="Huang C" first="Canhua" last="Huang">Canhua Huang</name>
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<author><name sortKey="Li, Yue Nan" sort="Li, Yue Nan" uniqKey="Li Y" first="Yue-Nan" last="Li">Yue-Nan Li</name>
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<author><name sortKey="Dai, Hao Fu" sort="Dai, Hao Fu" uniqKey="Dai H" first="Hao-Fu" last="Dai">Hao-Fu Dai</name>
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<author><name sortKey="Tan, Guang Hong" sort="Tan, Guang Hong" uniqKey="Tan G" first="Guang-Hong" last="Tan">Guang-Hong Tan</name>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term>
<term>Antineoplastic Agents (administration & dosage)</term>
<term>Antineoplastic Agents (pharmacology)</term>
<term>Autophagy (drug effects)</term>
<term>Blotting, Western</term>
<term>Cardenolides (administration & dosage)</term>
<term>Cardenolides (pharmacology)</term>
<term>Cell Line, Tumor</term>
<term>Cell Proliferation (drug effects)</term>
<term>Cell Survival (drug effects)</term>
<term>Disease Models, Animal</term>
<term>Flow Cytometry</term>
<term>Fluorescent Antibody Technique</term>
<term>Formazans (analysis)</term>
<term>Gene Expression Profiling</term>
<term>HSP90 Heat-Shock Proteins (metabolism)</term>
<term>Humans</term>
<term>Lung Neoplasms (drug therapy)</term>
<term>Mice, Inbred BALB C</term>
<term>Mice, Nude</term>
<term>Microscopy, Electron, Transmission</term>
<term>Neoplasm Transplantation</term>
<term>Oncogene Protein v-akt (metabolism)</term>
<term>Real-Time Polymerase Chain Reaction</term>
<term>Reverse Transcriptase Polymerase Chain Reaction</term>
<term>Signal Transduction (drug effects)</term>
<term>Staining and Labeling</term>
<term>TOR Serine-Threonine Kinases (metabolism)</term>
<term>Tetrazolium Salts (analysis)</term>
<term>Treatment Outcome</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Analyse de profil d'expression de gènes</term>
<term>Animaux</term>
<term>Antinéoplasiques (administration et posologie)</term>
<term>Antinéoplasiques (pharmacologie)</term>
<term>Autophagie ()</term>
<term>Cardénolides (administration et posologie)</term>
<term>Cardénolides (pharmacologie)</term>
<term>Coloration et marquage</term>
<term>Cytométrie en flux</term>
<term>Formazanes (analyse)</term>
<term>Humains</term>
<term>Lignée cellulaire tumorale</term>
<term>Microscopie électronique à transmission</term>
<term>Modèles animaux de maladie humaine</term>
<term>Prolifération cellulaire ()</term>
<term>Protéine oncogène v-akt (métabolisme)</term>
<term>Protéines du choc thermique HSP90 (métabolisme)</term>
<term>RT-PCR</term>
<term>Réaction de polymérisation en chaine en temps réel</term>
<term>Résultat thérapeutique</term>
<term>Sels de tétrazolium (analyse)</term>
<term>Souris de lignée BALB C</term>
<term>Souris nude</term>
<term>Survie cellulaire ()</term>
<term>Sérine-thréonine kinases TOR (métabolisme)</term>
<term>Technique d'immunofluorescence</term>
<term>Technique de Western</term>
<term>Transduction du signal ()</term>
<term>Transplantation tumorale</term>
<term>Tumeurs du poumon (traitement médicamenteux)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="administration & dosage" xml:lang="en"><term>Antineoplastic Agents</term>
<term>Cardenolides</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="analysis" xml:lang="en"><term>Formazans</term>
<term>Tetrazolium Salts</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>HSP90 Heat-Shock Proteins</term>
<term>Oncogene Protein v-akt</term>
<term>TOR Serine-Threonine Kinases</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antineoplastic Agents</term>
<term>Cardenolides</term>
</keywords>
<keywords scheme="MESH" qualifier="administration et posologie" xml:lang="fr"><term>Antinéoplasiques</term>
<term>Cardénolides</term>
</keywords>
<keywords scheme="MESH" qualifier="analyse" xml:lang="fr"><term>Formazanes</term>
<term>Sels de tétrazolium</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Autophagy</term>
<term>Cell Proliferation</term>
<term>Cell Survival</term>
<term>Signal Transduction</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Lung Neoplasms</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Protéine oncogène v-akt</term>
<term>Protéines du choc thermique HSP90</term>
<term>Sérine-thréonine kinases TOR</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antinéoplasiques</term>
<term>Cardénolides</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Tumeurs du poumon</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Blotting, Western</term>
<term>Cell Line, Tumor</term>
<term>Disease Models, Animal</term>
<term>Flow Cytometry</term>
<term>Fluorescent Antibody Technique</term>
<term>Gene Expression Profiling</term>
<term>Humans</term>
<term>Mice, Inbred BALB C</term>
<term>Mice, Nude</term>
<term>Microscopy, Electron, Transmission</term>
<term>Neoplasm Transplantation</term>
<term>Real-Time Polymerase Chain Reaction</term>
<term>Reverse Transcriptase Polymerase Chain Reaction</term>
<term>Staining and Labeling</term>
<term>Treatment Outcome</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Analyse de profil d'expression de gènes</term>
<term>Animaux</term>
<term>Autophagie</term>
<term>Coloration et marquage</term>
<term>Cytométrie en flux</term>
<term>Humains</term>
<term>Lignée cellulaire tumorale</term>
<term>Microscopie électronique à transmission</term>
<term>Modèles animaux de maladie humaine</term>
<term>Prolifération cellulaire</term>
<term>RT-PCR</term>
<term>Réaction de polymérisation en chaine en temps réel</term>
<term>Résultat thérapeutique</term>
<term>Souris de lignée BALB C</term>
<term>Souris nude</term>
<term>Survie cellulaire</term>
<term>Technique d'immunofluorescence</term>
<term>Technique de Western</term>
<term>Transduction du signal</term>
<term>Transplantation tumorale</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><b>Rationale:</b>
Cardenolides have potential as anticancer drugs. 3'-epi-12β-hydroxyfroside (HyFS) is a new cardenolide structure isolated by our research group, but its molecular mechanisms remain poorly understood. This study investigates the relationship between its antitumor activities and autophagy in lung cancer cells. <b>Methods:</b>
Cell growth and proliferation were detected by MTT, lactate dehydrogenase (LDH) release, 5-ethynyl-20-deoxyuridine (EDU) and colony formation assays. Cell apoptosis was detected by flow cytometry. Autophagic and signal proteins were detected by Western blotting. Markers of autophagy and autophagy flux were also detected by immunofluorescence, transmission electron microscopy and acridine orange staining. Real time RT-PCR was used to analyze the gene expression of Hsp90. Hsp90 ubiquitination was detected by coimmunoprecipitation. The antitumore activities of HyFS were observed in nude mice. <b>Results:</b>
HyFS treatment inhibited cell proliferation and induced autophagy in A549 and H460 lung cancer cells, but stronger inhibition of cell proliferation and induction of cell apoptosis were shown when HyFS-mediated autophagy was blocked. The Hsp90/Akt/mTOR axis was found to be involved in the activation of HyFS-mediated autophagy. Evidence of direct interaction between Hsp90 and Akt was observed. HyFS treatment resulted in decreased levels of heat shock protein 90 (Hsp90) and phosphorylated Akt, overexpression of Hsp90 increased activation of autophagy, and inhibition of Hsp90 expression decreased autophagy. In addition, ubiquitin-mediated degradation of Hsp90 and subsequent dephosphorylation of its client protein Akt were also found in HyFS-treated lung cancer cells. Moreover, combination treatment with HyFS and chloroquine showed remarkably increased tumor inhibition in both A549- and H460-bearing mice. <b>Conclusion:</b>
Our results demonstrate that HyFS induced cytoprotective autophagy through ubiquitin-mediated degradation of Hsp90, which further blocked the Akt/mTOR pathway in lung cancer cells. Thus, a combination of a HyFS-like cardenolide and an autophagic inhibitor is a potential alternative approach for the treatment of lung cancer.</div>
</front>
</TEI>
<affiliations><list><country><li>République populaire de Chine</li>
</country>
</list>
<tree><country name="République populaire de Chine"><noRegion><name sortKey="Sun, Yan" sort="Sun, Yan" uniqKey="Sun Y" first="Yan" last="Sun">Yan Sun</name>
</noRegion>
<name sortKey="Dai, Hao Fu" sort="Dai, Hao Fu" uniqKey="Dai H" first="Hao-Fu" last="Dai">Hao-Fu Dai</name>
<name sortKey="Huang, Canhua" sort="Huang, Canhua" uniqKey="Huang C" first="Canhua" last="Huang">Canhua Huang</name>
<name sortKey="Huang, Feng Ying" sort="Huang, Feng Ying" uniqKey="Huang F" first="Feng-Ying" last="Huang">Feng-Ying Huang</name>
<name sortKey="Huang, Yong Hao" sort="Huang, Yong Hao" uniqKey="Huang Y" first="Yong-Hao" last="Huang">Yong-Hao Huang</name>
<name sortKey="Li, Yue Nan" sort="Li, Yue Nan" uniqKey="Li Y" first="Yue-Nan" last="Li">Yue-Nan Li</name>
<name sortKey="Lin, Ying Ying" sort="Lin, Ying Ying" uniqKey="Lin Y" first="Ying-Ying" last="Lin">Ying-Ying Lin</name>
<name sortKey="Liu, Quan" sort="Liu, Quan" uniqKey="Liu Q" first="Quan" last="Liu">Quan Liu</name>
<name sortKey="Mei, Wen Li" sort="Mei, Wen Li" uniqKey="Mei W" first="Wen-Li" last="Mei">Wen-Li Mei</name>
<name sortKey="Tan, Guang Hong" sort="Tan, Guang Hong" uniqKey="Tan G" first="Guang-Hong" last="Tan">Guang-Hong Tan</name>
<name sortKey="Wang, Cai Chun" sort="Wang, Cai Chun" uniqKey="Wang C" first="Cai-Chun" last="Wang">Cai-Chun Wang</name>
</country>
</tree>
</affiliations>
</record>
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