Akt/mTOR-Mediated Autophagy Confers Resistance To BET Inhibitor JQ1 In Ovarian Cancer
Identifieur interne : 000B00 ( Main/Exploration ); précédent : 000A99; suivant : 000B01Akt/mTOR-Mediated Autophagy Confers Resistance To BET Inhibitor JQ1 In Ovarian Cancer
Auteurs : Wenqing Luan [République populaire de Chine] ; Yingxin Pang [République populaire de Chine] ; Rui Li [République populaire de Chine] ; Xuan Wei [République populaire de Chine] ; Xiaoxiao Jiao [République populaire de Chine] ; Juanjuan Shi [République populaire de Chine] ; Jiangtao Yu [République populaire de Chine] ; Hongluan Mao [République populaire de Chine] ; Peishu Liu [République populaire de Chine]Source :
- OncoTargets and therapy [ 1178-6930 ] ; 2019.
Abstract
Bromodomain and extra-terminal domain inhibitors like JQ1 have proved to be promising epigenetic agents for the treatment of malignant ovarian carcinoma. However, the resistance of ovarian cancer cells to BET inhibitors has not been elucidated. In this study, we investigated the potential mechanisms underlying the resistance of ovarian cancer cell lines to the BET inhibitor JQ1.
We evaluated the apoptotic and proliferative response of four ovarian cancer cell lines to JQ1. The cell lines were designated as resistant (A2780 and HO-8910) and sensitive groups (SKOV-3 and HEY). Further experiments detected the different levels of JQ1-induced autophagy. Anti-tumour effect of the combination of JQ1 and autophagy inhibitors was tested both in vitro and in vivo.
In the JQ1-sensitive group, JQ1 effectively inhibited proliferation and apoptosis in a concentration-dependent manner. Conversely, JQ1 showed modest inhibition of proliferation and negligible apoptosis in the resistant group. We detected increased LC3-II lipidation, autophagosome formation, upregulation of Beclin-1 and ATG5, and downregulation of P62/SQSTM1 in the resistant group. Inhibition of JQ1-induced autophagy by pharmacologic inhibitors 3-MA and CQ enhanced the inhibition of proliferation and significantly increased the apoptosis in the JQ1-resistant group, which was also verified by in vivo experiments, indicating that JQ1-induced autophagy played a cytoprotective role. Inactivation of Akt (Ser473)/mTOR(Ser2448) pathway was associated with JQ1-induced autophagy in the resistant group. Overexpression of Akt1 suppressed autophagy and increased the anti-tumour effect of JQ1.
These findings revealed that JQ1-induced pro-survival autophagy might be a potential mechanism in the resistance of ovarian cancer cells to BET inhibition by JQ1. Combination of JQ1 and autophagy inhibitors could be an effective therapeutic strategy for overcoming BET inhibitor resistance in ovarian cancer.
Url:
DOI: 10.2147/OTT.S220267
PubMed: 31632060
PubMed Central: 6781612
Affiliations:
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Hongluan" sort="Mao, Hongluan" uniqKey="Mao H" first="Hongluan" last="Mao">Hongluan Mao</name><affiliation wicri:level="1"><nlm:aff id="AFF0001"><institution>Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University</institution>,<addr-line>Jinan</addr-line><addr-line>250012</addr-line>,<country>People’s Republic of 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, Peishu" sort="Liu, Peishu" uniqKey="Liu P" first="Peishu" last="Liu">Peishu Liu</name><affiliation wicri:level="1"><nlm:aff id="AFF0001"><institution>Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University</institution>,<addr-line>Jinan</addr-line><addr-line>250012</addr-line>,<country>People’s Republic of China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country 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id="AFF0001"><institution>Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University</institution>,<addr-line>Jinan</addr-line><addr-line>250012</addr-line>,<country>People’s Republic of 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="Li, Rui" sort="Li, Rui" uniqKey="Li R" first="Rui" last="Li">Rui Li</name><affiliation wicri:level="1"><nlm:aff id="AFF0001"><institution>Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University</institution>,<addr-line>Jinan</addr-line><addr-line>250012</addr-line>,<country>People’s Republic of 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="Wei, Xuan" sort="Wei, Xuan" uniqKey="Wei X" first="Xuan" last="Wei">Xuan Wei</name><affiliation wicri:level="1"><nlm:aff id="AFF0001"><institution>Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University</institution>,<addr-line>Jinan</addr-line><addr-line>250012</addr-line>,<country>People’s Republic of 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="Jiao, Xiaoxiao" sort="Jiao, Xiaoxiao" uniqKey="Jiao X" first="Xiaoxiao" last="Jiao">Xiaoxiao Jiao</name><affiliation wicri:level="1"><nlm:aff id="AFF0002"><institution>Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University</institution>,<addr-line>Zhengzhou</addr-line><addr-line>450052</addr-line>,<country>People’s Republic of 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="Shi, Juanjuan" sort="Shi, Juanjuan" uniqKey="Shi J" first="Juanjuan" last="Shi">Juanjuan Shi</name><affiliation wicri:level="1"><nlm:aff id="AFF0001"><institution>Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University</institution>,<addr-line>Jinan</addr-line><addr-line>250012</addr-line>,<country>People’s Republic of 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="Yu, Jiangtao" sort="Yu, Jiangtao" uniqKey="Yu J" first="Jiangtao" last="Yu">Jiangtao Yu</name><affiliation wicri:level="1"><nlm:aff id="AFF0001"><institution>Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University</institution>,<addr-line>Jinan</addr-line><addr-line>250012</addr-line>,<country>People’s Republic of 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="Mao, Hongluan" sort="Mao, Hongluan" uniqKey="Mao H" first="Hongluan" last="Mao">Hongluan Mao</name><affiliation wicri:level="1"><nlm:aff id="AFF0001"><institution>Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University</institution>,<addr-line>Jinan</addr-line><addr-line>250012</addr-line>,<country>People’s Republic of 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, Peishu" sort="Liu, Peishu" uniqKey="Liu P" first="Peishu" last="Liu">Peishu Liu</name><affiliation wicri:level="1"><nlm:aff id="AFF0001"><institution>Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University</institution>,<addr-line>Jinan</addr-line><addr-line>250012</addr-line>,<country>People’s Republic of 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">OncoTargets and therapy</title><idno type="eISSN">1178-6930</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="S2001"><title>Background</title><p>Bromodomain and extra-terminal domain inhibitors like JQ1 have proved to be promising epigenetic agents for the treatment of malignant ovarian carcinoma. However, the resistance of ovarian cancer cells to BET inhibitors has not been elucidated. In this study, we investigated the potential mechanisms underlying the resistance of ovarian cancer cell lines to the BET inhibitor JQ1.</p></sec><sec id="S2002"><title>Materials and methods</title><p>We evaluated the apoptotic and proliferative response of four ovarian cancer cell lines to JQ1. The cell lines were designated as resistant (A2780 and HO-8910) and sensitive groups (SKOV-3 and HEY). Further experiments detected the different levels of JQ1-induced autophagy. Anti-tumour effect of the combination of JQ1 and autophagy inhibitors was tested both in vitro and in vivo.</p></sec><sec id="S2003"><title>Results</title><p>In the JQ1-sensitive group, JQ1 effectively inhibited proliferation and apoptosis in a concentration-dependent manner. Conversely, JQ1 showed modest inhibition of proliferation and negligible apoptosis in the resistant group. We detected increased LC3-II lipidation, autophagosome formation, upregulation of Beclin-1 and ATG5, and downregulation of P62/SQSTM1 in the resistant group. Inhibition of JQ1-induced autophagy by pharmacologic inhibitors 3-MA and CQ enhanced the inhibition of proliferation and significantly increased the apoptosis in the JQ1-resistant group, which was also verified by in vivo experiments, indicating that JQ1-induced autophagy played a cytoprotective role. Inactivation of Akt (Ser473)/mTOR(Ser2448) pathway was associated with JQ1-induced autophagy in the resistant group. Overexpression of Akt1 suppressed autophagy and increased the anti-tumour effect of JQ1.</p></sec><sec id="S2004"><title>Conclusion</title><p>These findings revealed that JQ1-induced pro-survival autophagy might be a potential mechanism in the resistance of ovarian cancer cells to BET inhibition by JQ1. Combination of JQ1 and autophagy inhibitors could be an effective therapeutic strategy for overcoming BET inhibitor resistance in ovarian cancer.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></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="Luan, Wenqing" sort="Luan, Wenqing" uniqKey="Luan W" first="Wenqing" last="Luan">Wenqing Luan</name></noRegion><name sortKey="Jiao, Xiaoxiao" sort="Jiao, Xiaoxiao" uniqKey="Jiao X" first="Xiaoxiao" last="Jiao">Xiaoxiao Jiao</name><name sortKey="Li, Rui" sort="Li, Rui" uniqKey="Li R" first="Rui" last="Li">Rui Li</name><name sortKey="Liu, Peishu" sort="Liu, Peishu" uniqKey="Liu P" first="Peishu" last="Liu">Peishu Liu</name><name sortKey="Mao, Hongluan" sort="Mao, Hongluan" uniqKey="Mao H" first="Hongluan" last="Mao">Hongluan Mao</name><name sortKey="Pang, Yingxin" sort="Pang, Yingxin" uniqKey="Pang Y" first="Yingxin" last="Pang">Yingxin Pang</name><name sortKey="Shi, Juanjuan" sort="Shi, Juanjuan" uniqKey="Shi J" first="Juanjuan" last="Shi">Juanjuan Shi</name><name sortKey="Wei, Xuan" sort="Wei, Xuan" uniqKey="Wei X" first="Xuan" last="Wei">Xuan Wei</name><name sortKey="Yu, Jiangtao" sort="Yu, Jiangtao" uniqKey="Yu J" first="Jiangtao" last="Yu">Jiangtao Yu</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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