ZSTK474, a specific class I phosphatidylinositol 3-kinase inhibitor, induces G1 arrest and autophagy in human breast cancer MCF-7 cells
Identifieur interne : 000909 ( Main/Exploration ); précédent : 000908; suivant : 000910ZSTK474, a specific class I phosphatidylinositol 3-kinase inhibitor, induces G1 arrest and autophagy in human breast cancer MCF-7 cells
Auteurs : Yaochen Wang [République populaire de Chine] ; Jing Liu [République populaire de Chine] ; Yuling Qiu [République populaire de Chine] ; Meihua Jin [République populaire de Chine] ; Xi Chen [République populaire de Chine] ; Guanwei Fan [République populaire de Chine] ; Ran Wang [République populaire de Chine] ; Dexin Kong [République populaire de Chine]Source :
- Oncotarget [ 1949-2553 ] ; 2016.
Abstract
Multifaceted activities of class I phosphatidylinositol 3-kinase (PI3K) inhibitor ZSTK474 were investigated on human breast cancer cell MCF-7. ZSTK474 inhibited proliferation of MCF-7 cells potently. Flow cytometric analysis indicated that ZSTK474 induced cell cycle arrest at G1 phase, but no obvious apoptosis occurred. Western blot analysis suggested that blockade of PI3K/Akt/GSK-3β/cyclin D1/p-Rb pathway might contribute to the G1 arrest induced. Moreover, we demonstrated that ZSTK474 induced autophagy in MCF-7 cells by use of various assays including monodansylcadaverine (MDC) staining, transmission electron microscopy (TEM), tandem mRFP-GFP-LC3 fluorescence microscopy, and western blot detection of the autophagy protein markers of LC3B II, p62 and Atg 5. Inhibition of class I PI3K and the downstream mTOR might be involved in the autophagy-inducing effect. Combinational use of ZSTK474 and autophagy inhibitors enhanced cell viability, suggesting ZSTK474-induced autophagy might contribute to the antitumor activity. Our report supports the application of ZSTK474, which is being evaluated in clinical trials, for breast cancer therapy.
Url:
DOI: 10.18632/oncotarget.7658
PubMed: 26918351
PubMed Central: 4991426
Affiliations:
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Tianjin University of Traditional Chinese Medicine, Nankai Dsitrict, Tianjin 300193, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea> State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Nankai Dsitrict, Tianjin 300193</wicri:regionArea><placeName><settlement type="city">Tianjin</settlement></placeName></affiliation></author><author><name sortKey="Wang, Ran" sort="Wang, Ran" uniqKey="Wang R" first="Ran" last="Wang">Ran Wang</name><affiliation wicri:level="1"><nlm:aff id="A1"> Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea> Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070</wicri:regionArea><placeName><settlement type="city">Tianjin</settlement></placeName></affiliation></author><author><name sortKey="Kong, Dexin" sort="Kong, Dexin" uniqKey="Kong D" first="Dexin" last="Kong">Dexin Kong</name><affiliation wicri:level="1"><nlm:aff id="A1"> Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea> Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070</wicri:regionArea><placeName><settlement type="city">Tianjin</settlement></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="A2"> Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, 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Chine</country><wicri:regionArea> Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070</wicri:regionArea><placeName><settlement type="city">Tianjin</settlement></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="A2"> Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea> Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070</wicri:regionArea><placeName><settlement type="city">Tianjin</settlement></placeName></affiliation></author><author><name sortKey="Liu, Jing" sort="Liu, Jing" uniqKey="Liu J" first="Jing" last="Liu">Jing Liu</name><affiliation wicri:level="1"><nlm:aff id="A1"> Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea> Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070</wicri:regionArea><placeName><settlement type="city">Tianjin</settlement></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="A2"> Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea> Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070</wicri:regionArea><placeName><settlement type="city">Tianjin</settlement></placeName></affiliation></author><author><name sortKey="Qiu, Yuling" sort="Qiu, Yuling" uniqKey="Qiu Y" first="Yuling" last="Qiu">Yuling Qiu</name><affiliation wicri:level="1"><nlm:aff id="A1"> Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea> Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070</wicri:regionArea><placeName><settlement type="city">Tianjin</settlement></placeName></affiliation></author><author><name sortKey="Jin, Meihua" sort="Jin, Meihua" uniqKey="Jin M" first="Meihua" last="Jin">Meihua Jin</name><affiliation wicri:level="1"><nlm:aff id="A1"> Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea> Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070</wicri:regionArea><placeName><settlement type="city">Tianjin</settlement></placeName></affiliation></author><author><name sortKey="Chen, Xi" sort="Chen, Xi" uniqKey="Chen X" first="Xi" last="Chen">Xi Chen</name><affiliation wicri:level="1"><nlm:aff id="A1"> Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea> Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070</wicri:regionArea><placeName><settlement type="city">Tianjin</settlement></placeName></affiliation></author><author><name sortKey="Fan, Guanwei" sort="Fan, Guanwei" uniqKey="Fan G" first="Guanwei" last="Fan">Guanwei Fan</name><affiliation wicri:level="1"><nlm:aff id="A3"> State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Nankai Dsitrict, Tianjin 300193, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea> State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Nankai Dsitrict, Tianjin 300193</wicri:regionArea><placeName><settlement type="city">Tianjin</settlement></placeName></affiliation></author><author><name sortKey="Wang, Ran" sort="Wang, Ran" uniqKey="Wang R" first="Ran" last="Wang">Ran Wang</name><affiliation wicri:level="1"><nlm:aff id="A1"> Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea> Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070</wicri:regionArea><placeName><settlement type="city">Tianjin</settlement></placeName></affiliation></author><author><name sortKey="Kong, Dexin" sort="Kong, Dexin" uniqKey="Kong D" first="Dexin" last="Kong">Dexin Kong</name><affiliation wicri:level="1"><nlm:aff id="A1"> Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea> Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070</wicri:regionArea><placeName><settlement type="city">Tianjin</settlement></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="A2"> Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea> Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070</wicri:regionArea><placeName><settlement type="city">Tianjin</settlement></placeName></affiliation></author></analytic><series><title level="j">Oncotarget</title><idno type="eISSN">1949-2553</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Multifaceted activities of class I phosphatidylinositol 3-kinase (PI3K) inhibitor ZSTK474 were investigated on human breast cancer cell MCF-7. ZSTK474 inhibited proliferation of MCF-7 cells potently. Flow cytometric analysis indicated that ZSTK474 induced cell cycle arrest at G1 phase, but no obvious apoptosis occurred. Western blot analysis suggested that blockade of PI3K/Akt/GSK-3β/cyclin D1/p-Rb pathway might contribute to the G1 arrest induced. Moreover, we demonstrated that ZSTK474 induced autophagy in MCF-7 cells by use of various assays including monodansylcadaverine (MDC) staining, transmission electron microscopy (TEM), tandem mRFP-GFP-LC3 fluorescence microscopy, and western blot detection of the autophagy protein markers of LC3B II, p62 and Atg 5. Inhibition of class I PI3K and the downstream mTOR might be involved in the autophagy-inducing effect. Combinational use of ZSTK474 and autophagy inhibitors enhanced cell viability, suggesting ZSTK474-induced autophagy might contribute to the antitumor activity. Our report supports the application of ZSTK474, which is being evaluated in clinical trials, for breast cancer therapy.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Torre, La" uniqKey="Torre L">LA Torre</name></author><author><name sortKey="Bray, F" uniqKey="Bray F">F Bray</name></author><author><name sortKey="Siegel, Rl" uniqKey="Siegel R">RL Siegel</name></author><author><name sortKey="Ferlay, J" uniqKey="Ferlay J">J Ferlay</name></author><author><name sortKey="Lortet Tieulent, J" uniqKey="Lortet Tieulent J">J Lortet-Tieulent</name></author><author><name sortKey="Jemal, A" uniqKey="Jemal A">A Jemal</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Desantis, Ce" uniqKey="Desantis C">CE DeSantis</name></author><author><name sortKey="Lin, Cc" uniqKey="Lin C">CC Lin</name></author><author><name sortKey="Mariotto, Ab" uniqKey="Mariotto A">AB Mariotto</name></author><author><name sortKey="Siegel, 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populaire de Chine</li></country><settlement><li>Tianjin</li></settlement></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Wang, Yaochen" sort="Wang, Yaochen" uniqKey="Wang Y" first="Yaochen" last="Wang">Yaochen Wang</name></noRegion><name sortKey="Chen, Xi" sort="Chen, Xi" uniqKey="Chen X" first="Xi" last="Chen">Xi Chen</name><name sortKey="Fan, Guanwei" sort="Fan, Guanwei" uniqKey="Fan G" first="Guanwei" last="Fan">Guanwei Fan</name><name sortKey="Jin, Meihua" sort="Jin, Meihua" uniqKey="Jin M" first="Meihua" last="Jin">Meihua Jin</name><name sortKey="Kong, Dexin" sort="Kong, Dexin" uniqKey="Kong D" first="Dexin" last="Kong">Dexin Kong</name><name sortKey="Kong, Dexin" sort="Kong, Dexin" uniqKey="Kong D" first="Dexin" last="Kong">Dexin Kong</name><name sortKey="Liu, Jing" sort="Liu, Jing" uniqKey="Liu J" first="Jing" last="Liu">Jing Liu</name><name sortKey="Liu, Jing" sort="Liu, Jing" uniqKey="Liu J" first="Jing" last="Liu">Jing Liu</name><name sortKey="Qiu, Yuling" sort="Qiu, Yuling" uniqKey="Qiu Y" first="Yuling" last="Qiu">Yuling Qiu</name><name sortKey="Wang, Ran" sort="Wang, Ran" uniqKey="Wang R" first="Ran" last="Wang">Ran Wang</name><name sortKey="Wang, Yaochen" sort="Wang, Yaochen" uniqKey="Wang Y" first="Yaochen" last="Wang">Yaochen Wang</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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