9za plays cytotoxic and proapoptotic roles and induces cytoprotective autophagy through the PDK1/Akt/mTOR axis in non-small-cell lung cancer.
Identifieur interne : 000053 ( PubMed/Corpus ); précédent : 000052; suivant : 0000549za plays cytotoxic and proapoptotic roles and induces cytoprotective autophagy through the PDK1/Akt/mTOR axis in non-small-cell lung cancer.
Auteurs : Rangru Liu ; Zhuo Chen ; Xinan Yi ; Fengying Huang ; Gaoyun Hu ; Danqi Liu ; Xi Li ; Honghao Zhou ; Zhaoqian LiuSource :
- Journal of cellular physiology [ 1097-4652 ] ; 2019.
Abstract
Non-small-cell lung cancer (NSCLC) is an aggressive subtype of pulmonary carcinomas with high mortality. However, chemotherapy drug resistance and high recurrence rates hinder the curative effect of platinum-based first-line chemotherapy, which makes it urgent to develop new antitumor drugs for NSCLC. 9za, a new candidate drug synthesized by our research group, has been verified with potent antilung cancer activity in preliminary experiments. However, the underlying molecular mechanism of 9za remains largely vague. This work revealed that 9za could play important cytotoxic and proapoptotic roles in NSCLC cells. Moreover, 9za could induce autophagy and promote autophagy flux. Interestingly, the cytotoxic and proapoptotic roles were significantly dependent on 9za-induced cytoprotective autophagy. That is, the coadministration of 9za with an autophagy inhibitor such as chloroquine or 3-methyladenine exhibited increased cytotoxic and proapoptotic effects compared with 9za treatment alone. In addition, 9za exposure suppressed the phosphorylation of phosphoinositide-dependent protein kinase 1 (PDK1), protein kinase B (Akt), mammalian targets of rapamycin (mTOR), p70 S6 kinase, and 4E binding protein 1 by a dose-dependent way, manifesting that the Akt/mTOR axis was implicated in 9za-induced autophagy. In addition, the overexpression of PDK1 resulted in increased phosphorylation of PDK1 and Akt and blocking of 9za-mediated autophagy. These data showed that the PDK1/Akt/mTOR pathway was involved in 9za-induced autophagy. Hence, this work provides a theoretical basis for exploiting 9za as a new antilung cancer candidate drug and hints that the combination of 9za with an autophagy inhibitor is a feasible alternative approach for the therapy of NSCLC.
DOI: 10.1002/jcp.28679
PubMed: 31004362
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Medical University and the Fourth Military Medical University, Haikou, Hainan, China.</nlm:affiliation></affiliation></author><author><name sortKey="Huang, Fengying" sort="Huang, Fengying" uniqKey="Huang F" first="Fengying" last="Huang">Fengying Huang</name><affiliation><nlm:affiliation>Key Laboratory of Tropical Diseases and Translational Medicine of the Ministry of Education, Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical University, Haikou, Hainan, China.</nlm:affiliation></affiliation></author><author><name sortKey="Hu, Gaoyun" sort="Hu, Gaoyun" uniqKey="Hu G" first="Gaoyun" last="Hu">Gaoyun Hu</name><affiliation><nlm:affiliation>Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China.</nlm:affiliation></affiliation></author><author><name sortKey="Liu, Danqi" sort="Liu, Danqi" uniqKey="Liu D" first="Danqi" last="Liu">Danqi Liu</name><affiliation><nlm:affiliation>Department of Pharmacy, Xiangya Hospital, Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, China.</nlm:affiliation></affiliation></author><author><name sortKey="Li, Xi" sort="Li, Xi" uniqKey="Li X" first="Xi" last="Li">Xi Li</name><affiliation><nlm:affiliation>Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China.</nlm:affiliation></affiliation></author><author><name sortKey="Zhou, Honghao" sort="Zhou, Honghao" uniqKey="Zhou H" first="Honghao" last="Zhou">Honghao Zhou</name><affiliation><nlm:affiliation>Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China.</nlm:affiliation></affiliation></author><author><name sortKey="Liu, Zhaoqian" sort="Liu, Zhaoqian" uniqKey="Liu Z" first="Zhaoqian" last="Liu">Zhaoqian Liu</name><affiliation><nlm:affiliation>Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2019">2019</date><idno type="RBID">pubmed:31004362</idno><idno type="pmid">31004362</idno><idno type="doi">10.1002/jcp.28679</idno><idno type="wicri:Area/PubMed/Corpus">000053</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000053</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">9za plays cytotoxic and proapoptotic roles and induces cytoprotective autophagy through the PDK1/Akt/mTOR axis in non-small-cell lung cancer.</title><author><name sortKey="Liu, Rangru" sort="Liu, Rangru" uniqKey="Liu R" first="Rangru" last="Liu">Rangru Liu</name><affiliation><nlm:affiliation>Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China.</nlm:affiliation></affiliation></author><author><name sortKey="Chen, Zhuo" sort="Chen, Zhuo" uniqKey="Chen Z" first="Zhuo" last="Chen">Zhuo Chen</name><affiliation><nlm:affiliation>Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China.</nlm:affiliation></affiliation></author><author><name sortKey="Yi, Xinan" sort="Yi, Xinan" uniqKey="Yi X" first="Xinan" last="Yi">Xinan Yi</name><affiliation><nlm:affiliation>The United Laboratory for Neurosciences of Hainan Medical University and the Fourth Military Medical University, Haikou, Hainan, China.</nlm:affiliation></affiliation></author><author><name sortKey="Huang, Fengying" sort="Huang, Fengying" uniqKey="Huang F" first="Fengying" last="Huang">Fengying Huang</name><affiliation><nlm:affiliation>Key Laboratory of Tropical Diseases and Translational Medicine of the Ministry of Education, Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical University, Haikou, Hainan, China.</nlm:affiliation></affiliation></author><author><name sortKey="Hu, Gaoyun" sort="Hu, Gaoyun" uniqKey="Hu G" first="Gaoyun" last="Hu">Gaoyun Hu</name><affiliation><nlm:affiliation>Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China.</nlm:affiliation></affiliation></author><author><name sortKey="Liu, Danqi" sort="Liu, Danqi" uniqKey="Liu D" first="Danqi" last="Liu">Danqi Liu</name><affiliation><nlm:affiliation>Department of Pharmacy, Xiangya Hospital, Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, China.</nlm:affiliation></affiliation></author><author><name sortKey="Li, Xi" sort="Li, Xi" uniqKey="Li X" first="Xi" last="Li">Xi Li</name><affiliation><nlm:affiliation>Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China.</nlm:affiliation></affiliation></author><author><name sortKey="Zhou, Honghao" sort="Zhou, Honghao" uniqKey="Zhou H" first="Honghao" last="Zhou">Honghao Zhou</name><affiliation><nlm:affiliation>Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China.</nlm:affiliation></affiliation></author><author><name sortKey="Liu, Zhaoqian" sort="Liu, Zhaoqian" uniqKey="Liu Z" first="Zhaoqian" last="Liu">Zhaoqian Liu</name><affiliation><nlm:affiliation>Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Journal of cellular physiology</title><idno type="eISSN">1097-4652</idno><imprint><date when="2019" type="published">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Non-small-cell lung cancer (NSCLC) is an aggressive subtype of pulmonary carcinomas with high mortality. However, chemotherapy drug resistance and high recurrence rates hinder the curative effect of platinum-based first-line chemotherapy, which makes it urgent to develop new antitumor drugs for NSCLC. 9za, a new candidate drug synthesized by our research group, has been verified with potent antilung cancer activity in preliminary experiments. However, the underlying molecular mechanism of 9za remains largely vague. This work revealed that 9za could play important cytotoxic and proapoptotic roles in NSCLC cells. Moreover, 9za could induce autophagy and promote autophagy flux. Interestingly, the cytotoxic and proapoptotic roles were significantly dependent on 9za-induced cytoprotective autophagy. That is, the coadministration of 9za with an autophagy inhibitor such as chloroquine or 3-methyladenine exhibited increased cytotoxic and proapoptotic effects compared with 9za treatment alone. In addition, 9za exposure suppressed the phosphorylation of phosphoinositide-dependent protein kinase 1 (PDK1), protein kinase B (Akt), mammalian targets of rapamycin (mTOR), p70 S6 kinase, and 4E binding protein 1 by a dose-dependent way, manifesting that the Akt/mTOR axis was implicated in 9za-induced autophagy. In addition, the overexpression of PDK1 resulted in increased phosphorylation of PDK1 and Akt and blocking of 9za-mediated autophagy. These data showed that the PDK1/Akt/mTOR pathway was involved in 9za-induced autophagy. Hence, this work provides a theoretical basis for exploiting 9za as a new antilung cancer candidate drug and hints that the combination of 9za with an autophagy inhibitor is a feasible alternative approach for the therapy of NSCLC.</div></front></TEI><pubmed><MedlineCitation Status="In-Data-Review" Owner="NLM"><PMID Version="1">31004362</PMID><DateRevised><Year>2019</Year><Month>07</Month><Day>26</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1097-4652</ISSN><JournalIssue CitedMedium="Internet"><Volume>234</Volume><Issue>11</Issue><PubDate><Year>2019</Year><Month>Nov</Month></PubDate></JournalIssue><Title>Journal of cellular physiology</Title><ISOAbbreviation>J. Cell. Physiol.</ISOAbbreviation></Journal><ArticleTitle>9za plays cytotoxic and proapoptotic roles and induces cytoprotective autophagy through the PDK1/Akt/mTOR axis in non-small-cell lung cancer.</ArticleTitle><Pagination><MedlinePgn>20728-20741</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1002/jcp.28679</ELocationID><Abstract><AbstractText>Non-small-cell lung cancer (NSCLC) is an aggressive subtype of pulmonary carcinomas with high mortality. However, chemotherapy drug resistance and high recurrence rates hinder the curative effect of platinum-based first-line chemotherapy, which makes it urgent to develop new antitumor drugs for NSCLC. 9za, a new candidate drug synthesized by our research group, has been verified with potent antilung cancer activity in preliminary experiments. However, the underlying molecular mechanism of 9za remains largely vague. This work revealed that 9za could play important cytotoxic and proapoptotic roles in NSCLC cells. Moreover, 9za could induce autophagy and promote autophagy flux. Interestingly, the cytotoxic and proapoptotic roles were significantly dependent on 9za-induced cytoprotective autophagy. That is, the coadministration of 9za with an autophagy inhibitor such as chloroquine or 3-methyladenine exhibited increased cytotoxic and proapoptotic effects compared with 9za treatment alone. In addition, 9za exposure suppressed the phosphorylation of phosphoinositide-dependent protein kinase 1 (PDK1), protein kinase B (Akt), mammalian targets of rapamycin (mTOR), p70 S6 kinase, and 4E binding protein 1 by a dose-dependent way, manifesting that the Akt/mTOR axis was implicated in 9za-induced autophagy. In addition, the overexpression of PDK1 resulted in increased phosphorylation of PDK1 and Akt and blocking of 9za-mediated autophagy. These data showed that the PDK1/Akt/mTOR pathway was involved in 9za-induced autophagy. Hence, this work provides a theoretical basis for exploiting 9za as a new antilung cancer candidate drug and hints that the combination of 9za with an autophagy inhibitor is a feasible alternative approach for the therapy of NSCLC.</AbstractText><CopyrightInformation>© 2019 Wiley Periodicals, Inc.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Liu</LastName><ForeName>Rangru</ForeName><Initials>R</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-5076-5146</Identifier><AffiliationInfo><Affiliation>Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Hunan Key Laboratory of Pharmacogenetics, National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Key Laboratory of Tropical Diseases and Translational Medicine of the Ministry of Education, Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical University, Haikou, Hainan, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chen</LastName><ForeName>Zhuo</ForeName><Initials>Z</Initials><AffiliationInfo><Affiliation>Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Yi</LastName><ForeName>Xinan</ForeName><Initials>X</Initials><AffiliationInfo><Affiliation>The United Laboratory for Neurosciences of Hainan Medical University and the Fourth Military Medical University, Haikou, Hainan, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Huang</LastName><ForeName>Fengying</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>Key Laboratory of Tropical Diseases and Translational Medicine of the Ministry of Education, Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical University, Haikou, Hainan, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hu</LastName><ForeName>Gaoyun</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Liu</LastName><ForeName>Danqi</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Department of Pharmacy, Xiangya Hospital, Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Li</LastName><ForeName>Xi</ForeName><Initials>X</Initials><AffiliationInfo><Affiliation>Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Hunan Key Laboratory of Pharmacogenetics, National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zhou</LastName><ForeName>Honghao</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Hunan Key Laboratory of Pharmacogenetics, National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Liu</LastName><ForeName>Zhaoqian</ForeName><Initials>Z</Initials><AffiliationInfo><Affiliation>Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Hunan Key Laboratory of Pharmacogenetics, National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>2016YFC1306900</GrantID><Agency>National Key Research and Development Program of China</Agency><Country></Country></Grant><Grant><GrantID>2016YFC0905002</GrantID><Agency>National Key Research and Development Program of China</Agency><Country></Country></Grant><Grant><GrantID>ZLXD2017003</GrantID><Agency>The Strategy-Oriented Special Project of Central South University in China</Agency><Country></Country></Grant><Grant><GrantID>ZDYF2016128</GrantID><Agency>Hainan Province Key Research and Development Project</Agency><Country></Country></Grant><Grant><GrantID>ZDYF2017092</GrantID><Agency>Hainan Province Key Research and Development Project</Agency><Country></Country></Grant><Grant><GrantID>2016JC2066</GrantID><Agency>Hunan Provincial Science and Technology Plan Project</Agency><Country></Country></Grant><Grant><GrantID>81874327</GrantID><Agency>National Natural Science Foundation of China</Agency><Country></Country></Grant><Grant><GrantID>81402968</GrantID><Agency>National Natural Science Foundation of China</Agency><Country></Country></Grant><Grant><GrantID>81573508</GrantID><Agency>National Natural Science Foundation of China</Agency><Country></Country></Grant><Grant><GrantID>2016GK4028</GrantID><Agency>Hunan Province Strategic Emerging Industry Science and Technology Key Project</Agency><Country></Country></Grant><Grant><GrantID>ZLXD2017003</GrantID><Agency>Central South University in China</Agency><Country></Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2019</Year><Month>04</Month><Day>19</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>J Cell Physiol</MedlineTA><NlmUniqueID>0050222</NlmUniqueID><ISSNLinking>0021-9541</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">9za</Keyword><Keyword MajorTopicYN="N">PDK1/Akt/mTOR signaling pathway</Keyword><Keyword MajorTopicYN="N">autophagy</Keyword><Keyword MajorTopicYN="N">cytotoxicity</Keyword><Keyword MajorTopicYN="N">non-small-cell lung cancer</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2018</Year><Month>11</Month><Day>03</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2019</Year><Month>03</Month><Day>24</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2019</Year><Month>04</Month><Day>02</Day></PubMedPubDate><PubMedPubDate 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