Ethanol Extract of Brucea javanica Seed Inhibit Triple-Negative Breast Cancer by Restraining Autophagy via PI3K/Akt/mTOR Pathway.
Identifieur interne : 000125 ( Main/Exploration ); précédent : 000124; suivant : 000126Ethanol Extract of Brucea javanica Seed Inhibit Triple-Negative Breast Cancer by Restraining Autophagy via PI3K/Akt/mTOR Pathway.
Auteurs : Xiaohong Chen [République populaire de Chine] ; Shuang Li [République populaire de Chine] ; Dan Li [République populaire de Chine] ; Muxia Li [République populaire de Chine] ; Ziren Su [République populaire de Chine] ; Xiaoping Lai [République populaire de Chine] ; Changlin Zhou [République populaire de Chine] ; Shaodan Chen [République populaire de Chine] ; Shunxian Li [République populaire de Chine] ; Xiaobing Yang [République populaire de Chine] ; Jiyan Su [République populaire de Chine] ; Yunjian Zhang [République populaire de Chine]Source :
- Frontiers in pharmacology [ 1663-9812 ] ; 2020.
Abstract
Triple-negative breast cancer (TNBC) is an aggressive disease with worst prognosis than other subtypes of breast cancer. Owing to the lack of hormone receptors and HER2 expression on TNBC cells, patients do not have targeted therapy options available with other breast cancer subtypes. Extensive efforts have been made to identify novel therapeutics against TNBC. Interestingly, recent studies had shown that plant-derived natural products could modulate the autophagy and induce the breast cancer cells death. Seed of Brucea javanica has been used as an important traditional Chinese medicine against cancers. In the present study, the anti-breast cancer potential of ethanol crude extracts from B. javanica seed (BJE) was explored. Data demonstrated that BJE could inhibit the TNBC cell line MDA-MB-231 proliferation and induced apoptosis. In the cells exposed to BJE, protein expressions of UNC-51-like kinase-1 (ULK1) and Beclin-1 and the ratio of light chain 3 II/I (LC3 II/I) were reduced, while the expression of p62 was increased, indicating an inhibition on autophagy. Moreover, BJE promoted the phosphorylation of mammalian target of rapamycin (mTOR), phosphatidylinositol 3-kinase (PI3K), and Akt in MDA-MB-231. BJE also suppressed the MDA-MB-231 tumor growth in vivo. Coincide with the results in vitro, autophagy in the tumor tissue was weakened as indicated by decreased ratio of LC 3 II/I and Beclin-1 accompanied by enhanced phosphorylation of mTOR, which confirmed that autophagy restraint via the PI3K/Akt/mTOR signaling pathway contributes to the suppression by BJE. Notably, no noticeable toxicity in non-targeted organs was found, including small intestine, liver, and kidney. Taken together, this study revealed anti-breast cancer activity of BJE based on autophagy restraint, highlighting its clinical importance as a novel natural agent against TNBC.
DOI: 10.3389/fphar.2020.00606
PubMed: 32411003
PubMed Central: PMC7201043
Affiliations:
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Li</name><affiliation wicri:level="3"><nlm:affiliation>Department of Thyroid and Breast Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Thyroid and Breast Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Li, Dan" sort="Li, Dan" uniqKey="Li D" first="Dan" last="Li">Dan Li</name><affiliation wicri:level="3"><nlm:affiliation>State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China.</nlm:affiliation><country 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Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Zhou, Changlin" sort="Zhou, Changlin" uniqKey="Zhou C" first="Changlin" last="Zhou">Changlin Zhou</name><affiliation wicri:level="1"><nlm:affiliation>Graduate School, Guangdong Medical University, Dongguan, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Graduate School, Guangdong Medical University, 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Ltd., Guangzhou, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Research and Development, Guangdong Yuewei Edible Fungi Technology Co. 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Guangzhou</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Su, Jiyan" sort="Su, Jiyan" uniqKey="Su J" first="Jiyan" last="Su">Jiyan Su</name><affiliation wicri:level="3"><nlm:affiliation>State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Zhang, Yunjian" sort="Zhang, Yunjian" uniqKey="Zhang Y" first="Yunjian" last="Zhang">Yunjian Zhang</name><affiliation wicri:level="3"><nlm:affiliation>Department of Thyroid and Breast Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Thyroid and Breast Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2020">2020</date><idno type="RBID">pubmed:32411003</idno><idno type="pmid">32411003</idno><idno type="doi">10.3389/fphar.2020.00606</idno><idno type="pmc">PMC7201043</idno><idno type="wicri:Area/Main/Corpus">000074</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000074</idno><idno type="wicri:Area/Main/Curation">000074</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000074</idno><idno type="wicri:Area/Main/Exploration">000074</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Ethanol Extract of <i>Brucea javanica</i> Seed Inhibit Triple-Negative Breast Cancer by Restraining Autophagy via PI3K/Akt/mTOR Pathway.</title><author><name sortKey="Chen, Xiaohong" sort="Chen, Xiaohong" uniqKey="Chen X" first="Xiaohong" last="Chen">Xiaohong Chen</name><affiliation wicri:level="3"><nlm:affiliation>State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation><affiliation wicri:level="3"><nlm:affiliation>Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Li, Shuang" sort="Li, Shuang" uniqKey="Li S" first="Shuang" last="Li">Shuang Li</name><affiliation wicri:level="3"><nlm:affiliation>Department of Thyroid and Breast Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Thyroid and Breast Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Li, Dan" sort="Li, Dan" uniqKey="Li D" first="Dan" last="Li">Dan Li</name><affiliation wicri:level="3"><nlm:affiliation>State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation><affiliation wicri:level="3"><nlm:affiliation>Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Li, Muxia" sort="Li, Muxia" uniqKey="Li M" first="Muxia" last="Li">Muxia Li</name><affiliation wicri:level="3"><nlm:affiliation>State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation><affiliation wicri:level="3"><nlm:affiliation>Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Su, Ziren" sort="Su, Ziren" uniqKey="Su Z" first="Ziren" last="Su">Ziren Su</name><affiliation wicri:level="3"><nlm:affiliation>Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Lai, Xiaoping" sort="Lai, Xiaoping" uniqKey="Lai X" first="Xiaoping" last="Lai">Xiaoping Lai</name><affiliation wicri:level="3"><nlm:affiliation>Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Zhou, Changlin" sort="Zhou, Changlin" uniqKey="Zhou C" first="Changlin" last="Zhou">Changlin Zhou</name><affiliation wicri:level="1"><nlm:affiliation>Graduate School, Guangdong Medical University, Dongguan, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Graduate School, Guangdong Medical University, Dongguan</wicri:regionArea><wicri:noRegion>Dongguan</wicri:noRegion></affiliation></author><author><name sortKey="Chen, Shaodan" sort="Chen, Shaodan" uniqKey="Chen S" first="Shaodan" last="Chen">Shaodan Chen</name><affiliation wicri:level="3"><nlm:affiliation>State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Li, Shunxian" sort="Li, Shunxian" uniqKey="Li S" first="Shunxian" last="Li">Shunxian Li</name><affiliation wicri:level="3"><nlm:affiliation>Department of Research and Development, Guangdong Yuewei Edible Fungi Technology Co. Ltd., Guangzhou, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Research and Development, Guangdong Yuewei Edible Fungi Technology Co. Ltd., Guangzhou</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Yang, Xiaobing" sort="Yang, Xiaobing" uniqKey="Yang X" first="Xiaobing" last="Yang">Xiaobing Yang</name><affiliation wicri:level="3"><nlm:affiliation>State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Su, Jiyan" sort="Su, Jiyan" uniqKey="Su J" first="Jiyan" last="Su">Jiyan Su</name><affiliation wicri:level="3"><nlm:affiliation>State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Zhang, Yunjian" sort="Zhang, Yunjian" uniqKey="Zhang Y" first="Yunjian" last="Zhang">Yunjian Zhang</name><affiliation wicri:level="3"><nlm:affiliation>Department of Thyroid and Breast Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Thyroid and Breast Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author></analytic><series><title level="j">Frontiers in pharmacology</title><idno type="ISSN">1663-9812</idno><imprint><date when="2020" type="published">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Triple-negative breast cancer (TNBC) is an aggressive disease with worst prognosis than other subtypes of breast cancer. Owing to the lack of hormone receptors and HER2 expression on TNBC cells, patients do not have targeted therapy options available with other breast cancer subtypes. Extensive efforts have been made to identify novel therapeutics against TNBC. Interestingly, recent studies had shown that plant-derived natural products could modulate the autophagy and induce the breast cancer cells death. Seed of <i>Brucea javanica</i> has been used as an important traditional Chinese medicine against cancers. In the present study, the anti-breast cancer potential of ethanol crude extracts from <i>B. javanica</i> seed (BJE) was explored. Data demonstrated that BJE could inhibit the TNBC cell line MDA-MB-231 proliferation and induced apoptosis. In the cells exposed to BJE, protein expressions of UNC-51-like kinase-1 (ULK1) and Beclin-1 and the ratio of light chain 3 II/I (LC3 II/I) were reduced, while the expression of p62 was increased, indicating an inhibition on autophagy. Moreover, BJE promoted the phosphorylation of mammalian target of rapamycin (mTOR), phosphatidylinositol 3-kinase (PI3K), and Akt in MDA-MB-231. BJE also suppressed the MDA-MB-231 tumor growth <i>in vivo</i>. Coincide with the results <i>in vitro</i>, autophagy in the tumor tissue was weakened as indicated by decreased ratio of LC 3 II/I and Beclin-1 accompanied by enhanced phosphorylation of mTOR, which confirmed that autophagy restraint via the PI3K/Akt/mTOR signaling pathway contributes to the suppression by BJE. Notably, no noticeable toxicity in non-targeted organs was found, including small intestine, liver, and kidney. Taken together, this study revealed anti-breast cancer activity of BJE based on autophagy restraint, highlighting its clinical importance as a novel natural agent against TNBC.</div></front></TEI><pubmed><MedlineCitation Status="PubMed-not-MEDLINE" Owner="NLM"><PMID Version="1">32411003</PMID><DateRevised><Year>2020</Year><Month>09</Month><Day>28</Day></DateRevised><Article PubModel="Electronic-eCollection"><Journal><ISSN IssnType="Print">1663-9812</ISSN><JournalIssue CitedMedium="Print"><Volume>11</Volume><PubDate><Year>2020</Year></PubDate></JournalIssue><Title>Frontiers in pharmacology</Title><ISOAbbreviation>Front Pharmacol</ISOAbbreviation></Journal><ArticleTitle>Ethanol Extract of <i>Brucea javanica</i> Seed Inhibit Triple-Negative Breast Cancer by Restraining Autophagy via PI3K/Akt/mTOR Pathway.</ArticleTitle><Pagination><MedlinePgn>606</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.3389/fphar.2020.00606</ELocationID><Abstract><AbstractText>Triple-negative breast cancer (TNBC) is an aggressive disease with worst prognosis than other subtypes of breast cancer. Owing to the lack of hormone receptors and HER2 expression on TNBC cells, patients do not have targeted therapy options available with other breast cancer subtypes. Extensive efforts have been made to identify novel therapeutics against TNBC. Interestingly, recent studies had shown that plant-derived natural products could modulate the autophagy and induce the breast cancer cells death. Seed of <i>Brucea javanica</i> has been used as an important traditional Chinese medicine against cancers. In the present study, the anti-breast cancer potential of ethanol crude extracts from <i>B. javanica</i> seed (BJE) was explored. Data demonstrated that BJE could inhibit the TNBC cell line MDA-MB-231 proliferation and induced apoptosis. In the cells exposed to BJE, protein expressions of UNC-51-like kinase-1 (ULK1) and Beclin-1 and the ratio of light chain 3 II/I (LC3 II/I) were reduced, while the expression of p62 was increased, indicating an inhibition on autophagy. Moreover, BJE promoted the phosphorylation of mammalian target of rapamycin (mTOR), phosphatidylinositol 3-kinase (PI3K), and Akt in MDA-MB-231. BJE also suppressed the MDA-MB-231 tumor growth <i>in vivo</i>. Coincide with the results <i>in vitro</i>, autophagy in the tumor tissue was weakened as indicated by decreased ratio of LC 3 II/I and Beclin-1 accompanied by enhanced phosphorylation of mTOR, which confirmed that autophagy restraint via the PI3K/Akt/mTOR signaling pathway contributes to the suppression by BJE. Notably, no noticeable toxicity in non-targeted organs was found, including small intestine, liver, and kidney. Taken together, this study revealed anti-breast cancer activity of BJE based on autophagy restraint, highlighting its clinical importance as a novel natural agent against TNBC.</AbstractText><CopyrightInformation>Copyright © 2020 Chen, Li, Li, Li, Su, Lai, Zhou, Chen, Li, Yang, Su and Zhang.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Chen</LastName><ForeName>Xiaohong</ForeName><Initials>X</Initials><AffiliationInfo><Affiliation>State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Li</LastName><ForeName>Shuang</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Thyroid and Breast Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Li</LastName><ForeName>Dan</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Li</LastName><ForeName>Muxia</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Su</LastName><ForeName>Ziren</ForeName><Initials>Z</Initials><AffiliationInfo><Affiliation>Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lai</LastName><ForeName>Xiaoping</ForeName><Initials>X</Initials><AffiliationInfo><Affiliation>Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zhou</LastName><ForeName>Changlin</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Graduate School, Guangdong Medical University, Dongguan, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chen</LastName><ForeName>Shaodan</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Li</LastName><ForeName>Shunxian</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Research and Development, Guangdong Yuewei Edible Fungi Technology Co. Ltd., Guangzhou, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Yang</LastName><ForeName>Xiaobing</ForeName><Initials>X</Initials><AffiliationInfo><Affiliation>State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Su</LastName><ForeName>Jiyan</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zhang</LastName><ForeName>Yunjian</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>Department of Thyroid and Breast Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2020</Year><Month>04</Month><Day>29</Day></ArticleDate></Article><MedlineJournalInfo><Country>Switzerland</Country><MedlineTA>Front Pharmacol</MedlineTA><NlmUniqueID>101548923</NlmUniqueID><ISSNLinking>1663-9812</ISSNLinking></MedlineJournalInfo><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Brucea javanica</Keyword><Keyword MajorTopicYN="N">PI3K/Akt/mTOR</Keyword><Keyword MajorTopicYN="N">autophagy</Keyword><Keyword MajorTopicYN="N">toxicity</Keyword><Keyword MajorTopicYN="N">triple-negative breast cancer (TNBC)</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2020</Year><Month>01</Month><Day>07</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2020</Year><Month>04</Month><Day>17</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2020</Year><Month>5</Month><Day>16</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2020</Year><Month>5</Month><Day>16</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2020</Year><Month>5</Month><Day>16</Day><Hour>6</Hour><Minute>1</Minute></PubMedPubDate></History><PublicationStatus>epublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">32411003</ArticleId><ArticleId IdType="doi">10.3389/fphar.2020.00606</ArticleId><ArticleId IdType="pmc">PMC7201043</ArticleId></ArticleIdList><ReferenceList><Reference><Citation>Clin Breast Cancer. 2016 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Dan" sort="Li, Dan" uniqKey="Li D" first="Dan" last="Li">Dan Li</name><name sortKey="Li, Dan" sort="Li, Dan" uniqKey="Li D" first="Dan" last="Li">Dan Li</name><name sortKey="Li, Muxia" sort="Li, Muxia" uniqKey="Li M" first="Muxia" last="Li">Muxia Li</name><name sortKey="Li, Muxia" sort="Li, Muxia" uniqKey="Li M" first="Muxia" last="Li">Muxia Li</name><name sortKey="Li, Shuang" sort="Li, Shuang" uniqKey="Li S" first="Shuang" last="Li">Shuang Li</name><name sortKey="Li, Shunxian" sort="Li, Shunxian" uniqKey="Li S" first="Shunxian" last="Li">Shunxian Li</name><name sortKey="Su, Jiyan" sort="Su, Jiyan" uniqKey="Su J" first="Jiyan" last="Su">Jiyan Su</name><name sortKey="Su, Ziren" sort="Su, Ziren" uniqKey="Su Z" first="Ziren" last="Su">Ziren Su</name><name sortKey="Yang, Xiaobing" sort="Yang, Xiaobing" uniqKey="Yang X" first="Xiaobing" last="Yang">Xiaobing Yang</name><name sortKey="Zhang, Yunjian" sort="Zhang, Yunjian" uniqKey="Zhang Y" first="Yunjian" last="Zhang">Yunjian 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