Oridonin Sensitizes Cisplatin-Induced Apoptosis via AMPK/Akt/mTOR-Dependent Autophagosome Accumulation in A549 Cells
Identifieur interne : 000567 ( Main/Exploration ); précédent : 000566; suivant : 000568Oridonin Sensitizes Cisplatin-Induced Apoptosis via AMPK/Akt/mTOR-Dependent Autophagosome Accumulation in A549 Cells
Auteurs : Huahong Yang [République populaire de Chine] ; Yun Gao [République populaire de Chine] ; Xiaoye Fan [République populaire de Chine] ; Xingkai Liu [République populaire de Chine] ; Liping Peng [République populaire de Chine] ; Xinxin Ci [République populaire de Chine]Source :
- Frontiers in Oncology [ 2234-943X ] ; 2019.
Abstract
AMPK-mediated autophagy and Akt/mTOR pathways play important roles in current cancer treatments. Oridonin (Ori), an ent-kaurane diterpenoid isolated from Isodon rubescens, exerts extensive anti-tumor potential and controversial effects on autophagy. In this study, we investigated the effect of Ori on the autophagy, apoptosis, and AMPK/Akt/mTOR pathways and determined whether Ori was related to the increased cisplatin sensitivity observed in A549 cells. First, we found that Ori suppressed Akt/mTOR, Bcl2 and autophagy flux with enhanced levels of Atg3, P62, and LC3II, which was also shown as the accumulation of autophagosomes. AMPK and pro-apoptotic proteins (caspase3, Bax, and PARP) were activated in Ori-treated cells. With the pretreatment of compound c (AMPK inhibitor), the activation of autophagosomes, apoptosis and the inhibition of Akt/mTOR pathways induced by Ori were all reversed. The Ori-activated apoptosis-related markers mentioned previously and the cell-killing effect were restrained by 3-MA (inhibitor of autophagosomes) treatment. Therefore, we hypothesized that the Ori-induced pro-apoptotic effect was mediated by AMPK/Akt/mTOR-dependent accumulation of impaired autophagosomes. Furthermore, Ori could increase the sensitivity of cisplatin through its increased cell-killing, autophagy-suppressing and apoptosis-inducing activities. In addition to sensitizing cisplatin, Ori also alleviated cisplatin-induced acute renal injury
Url:
DOI: 10.3389/fonc.2019.00769
PubMed: 31475112
PubMed Central: 6702493
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Oridonin Sensitizes Cisplatin-Induced Apoptosis via AMPK/Akt/mTOR-Dependent Autophagosome Accumulation in A549 Cells</title><author><name sortKey="Yang, Huahong" sort="Yang, Huahong" uniqKey="Yang H" first="Huahong" last="Yang">Huahong Yang</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Respiratory Medicine, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Gao, Yun" sort="Gao, Yun" uniqKey="Gao Y" first="Yun" last="Gao">Yun Gao</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Respiratory Medicine, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Fan, Xiaoye" sort="Fan, Xiaoye" uniqKey="Fan X" first="Xiaoye" last="Fan">Xiaoye Fan</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Institute of Translational Medicine, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Liu, Xingkai" sort="Liu, Xingkai" uniqKey="Liu X" first="Xingkai" last="Liu">Xingkai Liu</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Department of Hepatopancreatobiliary Surgery, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Peng, Liping" sort="Peng, Liping" uniqKey="Peng L" first="Liping" last="Peng">Liping Peng</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Respiratory Medicine, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Ci, Xinxin" sort="Ci, Xinxin" uniqKey="Ci X" first="Xinxin" last="Ci">Xinxin Ci</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Institute of Translational Medicine, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31475112</idno><idno type="pmc">6702493</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702493</idno><idno type="RBID">PMC:6702493</idno><idno type="doi">10.3389/fonc.2019.00769</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000563</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000563</idno><idno type="wicri:Area/Pmc/Curation">000563</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000563</idno><idno type="wicri:Area/Pmc/Checkpoint">000518</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000518</idno><idno type="wicri:Area/Ncbi/Merge">000983</idno><idno type="wicri:Area/Ncbi/Curation">000983</idno><idno type="wicri:Area/Ncbi/Checkpoint">000983</idno><idno type="wicri:Area/Main/Merge">000567</idno><idno type="wicri:Area/Main/Curation">000567</idno><idno type="wicri:Area/Main/Exploration">000567</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Oridonin Sensitizes Cisplatin-Induced Apoptosis via AMPK/Akt/mTOR-Dependent Autophagosome Accumulation in A549 Cells</title><author><name sortKey="Yang, Huahong" sort="Yang, Huahong" uniqKey="Yang H" first="Huahong" last="Yang">Huahong Yang</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Respiratory Medicine, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Gao, Yun" sort="Gao, Yun" uniqKey="Gao Y" first="Yun" last="Gao">Yun Gao</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Respiratory Medicine, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Fan, Xiaoye" sort="Fan, Xiaoye" uniqKey="Fan X" first="Xiaoye" last="Fan">Xiaoye Fan</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Institute of Translational Medicine, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Liu, Xingkai" sort="Liu, Xingkai" uniqKey="Liu X" first="Xingkai" last="Liu">Xingkai Liu</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Department of Hepatopancreatobiliary Surgery, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Peng, Liping" sort="Peng, Liping" uniqKey="Peng L" first="Liping" last="Peng">Liping Peng</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Respiratory Medicine, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Ci, Xinxin" sort="Ci, Xinxin" uniqKey="Ci X" first="Xinxin" last="Ci">Xinxin Ci</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Institute of Translational Medicine, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Frontiers in Oncology</title><idno type="eISSN">2234-943X</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>AMPK-mediated autophagy and Akt/mTOR pathways play important roles in current cancer treatments. Oridonin (Ori), an ent-kaurane diterpenoid isolated from Isodon rubescens, exerts extensive anti-tumor potential and controversial effects on autophagy. In this study, we investigated the effect of Ori on the autophagy, apoptosis, and AMPK/Akt/mTOR pathways and determined whether Ori was related to the increased cisplatin sensitivity observed in A549 cells. First, we found that Ori suppressed Akt/mTOR, Bcl2 and autophagy flux with enhanced levels of Atg3, P62, and LC3II, which was also shown as the accumulation of autophagosomes. AMPK and pro-apoptotic proteins (caspase3, Bax, and PARP) were activated in Ori-treated cells. With the pretreatment of compound c (AMPK inhibitor), the activation of autophagosomes, apoptosis and the inhibition of Akt/mTOR pathways induced by Ori were all reversed. The Ori-activated apoptosis-related markers mentioned previously and the cell-killing effect were restrained by 3-MA (inhibitor of autophagosomes) treatment. Therefore, we hypothesized that the Ori-induced pro-apoptotic effect was mediated by AMPK/Akt/mTOR-dependent accumulation of impaired autophagosomes. Furthermore, Ori could increase the sensitivity of cisplatin through its increased cell-killing, autophagy-suppressing and apoptosis-inducing activities. In addition to sensitizing cisplatin, Ori also alleviated cisplatin-induced acute renal injury <italic>in vivo</italic>, manifested as depleted BUN, CRE, kidney index, and weight loss compared to the cisplatin group. In summary, apart from its protective effect on cisplatin-induced nephrotoxicity, Ori enhanced cisplatin sensitivity via its pro-apoptotic activity mediated by AMPK/Akt/mTOR-dependent autophagosome activation, which may be a potential therapeutic target for non-small cell lung cancer.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Hirsch, Fr" uniqKey="Hirsch F">FR Hirsch</name></author><author><name sortKey="Suda, K" uniqKey="Suda K">K Suda</name></author><author><name sortKey="Wiens, J" uniqKey="Wiens J">J Wiens</name></author><author><name sortKey="Bunn, Pa" uniqKey="Bunn P">PA Bunn</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Neal, Rd" uniqKey="Neal R">RD Neal</name></author><author><name sortKey="Hamilton, W" uniqKey="Hamilton W">W Hamilton</name></author><author><name sortKey="Rogers, Tk" uniqKey="Rogers T">TK 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Cui</name></author><author><name sortKey="Wang, L" uniqKey="Wang L">L Wang</name></author><author><name sortKey="Zhao, L" uniqKey="Zhao L">L Zhao</name></author><author><name sortKey="Hou, C" uniqKey="Hou C">C Hou</name></author><author><name sortKey="Zeng, Q" uniqKey="Zeng Q">Q Zeng</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Crona, Dj" uniqKey="Crona D">DJ Crona</name></author><author><name sortKey="Faso, A" uniqKey="Faso A">A Faso</name></author><author><name sortKey="Nishijima, Tf" uniqKey="Nishijima T">TF Nishijima</name></author><author><name sortKey="Mcgraw, Ka" uniqKey="Mcgraw K">KA McGraw</name></author><author><name sortKey="Galsky, Md" uniqKey="Galsky M">MD Galsky</name></author><author><name sortKey="Milowsky, Mi" uniqKey="Milowsky M">MI Milowsky</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>République populaire de Chine</li></country></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Yang, Huahong" sort="Yang, Huahong" uniqKey="Yang H" first="Huahong" last="Yang">Huahong Yang</name></noRegion><name sortKey="Ci, Xinxin" sort="Ci, Xinxin" uniqKey="Ci X" first="Xinxin" last="Ci">Xinxin Ci</name><name sortKey="Fan, Xiaoye" sort="Fan, Xiaoye" uniqKey="Fan X" first="Xiaoye" last="Fan">Xiaoye Fan</name><name sortKey="Gao, Yun" sort="Gao, Yun" uniqKey="Gao Y" first="Yun" last="Gao">Yun Gao</name><name sortKey="Liu, Xingkai" sort="Liu, Xingkai" uniqKey="Liu X" first="Xingkai" last="Liu">Xingkai Liu</name><name sortKey="Peng, Liping" sort="Peng, Liping" uniqKey="Peng L" first="Liping" last="Peng">Liping Peng</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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