Induction of Apoptosis and Autophagy in Breast Cancer Cells by a Novel HDAC8 Inhibitor
Identifieur interne : 000735 ( Main/Exploration ); précédent : 000734; suivant : 000736Induction of Apoptosis and Autophagy in Breast Cancer Cells by a Novel HDAC8 Inhibitor
Auteurs : Chang-Fang Chiu [Taïwan] ; Hsien-Kuo Chin [Taïwan] ; Wei-Jan Huang ; Li-Yuan Bai [Taïwan] ; Hao-Yu Huang [Taïwan] ; Jing-Ru Weng [Taïwan]Source :
- Biomolecules [ 2218-273X ] ; 2019.
Abstract
Epigenetic therapy has been demonstrated to be a viable strategy for breast cancer treatment. In this study, we report the anti-tumor activity of a hydroxamate-based histone deacetylase (HDAC)8-selective inhibitor, HMC, in breast cancer cells. MTT assays showed that HMC inhibited cell viability of MCF-7 and MDA-MB-231 cells with IC50 values of 7.7 μM and 9.5 μM, respectively. HMC induced caspase-dependent apoptosis in MCF-7 cells, which was associated with its ability to modulate a series of cell survival-related signaling effectors, including Akt, mTOR, Bax, Mcl-1, and Bcl-2. Additionally, HMC was capable of activating PPARγ, which was accompanied by reduced expression of PPARγ target gene products, such as cyclin D1 and CDK6. HMC increased the production of ROS in MCF-7 cells, which could be partially reversed by the cotreatment with a ROS scavenger (
Url:
DOI: 10.3390/biom9120824
PubMed: 31817161
PubMed Central: 6995545
Affiliations:
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Taiwan;<email>d5686@mail.cmuh.org.tw</email> (C.-F.C.);<email>lybai6@gmail.com</email> (L.-Y.B.)</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af2-biomolecules-09-00824">Cancer Center, China Medical University Hospital, Taichung 40415, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Cancer Center, China Medical University Hospital, Taichung 40415</wicri:regionArea><wicri:noRegion>Taichung 40415</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af3-biomolecules-09-00824">College of Medicine, China Medical University, Taichung 40402, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>College of Medicine, China Medical University, Taichung 40402</wicri:regionArea><wicri:noRegion>Taichung 40402</wicri:noRegion></affiliation></author><author><name sortKey="Chin, Hsien Kuo" sort="Chin, Hsien Kuo" uniqKey="Chin H" first="Hsien-Kuo" last="Chin">Hsien-Kuo Chin</name><affiliation><nlm:aff id="af4-biomolecules-09-00824">Division of Cardiovascular Surgery, Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan;<email>cvschin@gmail.com</email></nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af5-biomolecules-09-00824">Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424</wicri:regionArea><wicri:noRegion>Kaohsiung 80424</wicri:noRegion></affiliation></author><author><name sortKey="Huang, Wei Jan" sort="Huang, Wei Jan" uniqKey="Huang W" first="Wei-Jan" last="Huang">Wei-Jan Huang</name><affiliation><nlm:aff id="af6-biomolecules-09-00824">Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan;<email>wjhuang@tmu.edu.tw</email></nlm:aff></affiliation></author><author><name sortKey="Bai, Li Yuan" sort="Bai, Li Yuan" uniqKey="Bai L" first="Li-Yuan" last="Bai">Li-Yuan Bai</name><affiliation><nlm:aff id="af1-biomolecules-09-00824">Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 40447, Taiwan;<email>d5686@mail.cmuh.org.tw</email> (C.-F.C.);<email>lybai6@gmail.com</email> (L.-Y.B.)</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af3-biomolecules-09-00824">College of Medicine, China Medical University, Taichung 40402, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>College of Medicine, China Medical University, Taichung 40402</wicri:regionArea><wicri:noRegion>Taichung 40402</wicri:noRegion></affiliation></author><author><name sortKey="Huang, Hao Yu" sort="Huang, Hao Yu" uniqKey="Huang H" first="Hao-Yu" last="Huang">Hao-Yu Huang</name><affiliation wicri:level="1"><nlm:aff id="af5-biomolecules-09-00824">Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424</wicri:regionArea><wicri:noRegion>Kaohsiung 80424</wicri:noRegion></affiliation></author><author><name sortKey="Weng, Jing Ru" sort="Weng, Jing Ru" uniqKey="Weng J" first="Jing-Ru" last="Weng">Jing-Ru Weng</name><affiliation wicri:level="1"><nlm:aff id="af5-biomolecules-09-00824">Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424</wicri:regionArea><wicri:noRegion>Kaohsiung 80424</wicri:noRegion></affiliation><affiliation><nlm:aff id="af6-biomolecules-09-00824">Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan;<email>wjhuang@tmu.edu.tw</email></nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af7-biomolecules-09-00824">Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University, Kaohsiung 80424, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University, Kaohsiung 80424</wicri:regionArea><wicri:noRegion>Kaohsiung 80424</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af8-biomolecules-09-00824">Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80715, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80715</wicri:regionArea><wicri:noRegion>Kaohsiung 80715</wicri:noRegion></affiliation></author></analytic><series><title level="j">Biomolecules</title><idno type="eISSN">2218-273X</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>Epigenetic therapy has been demonstrated to be a viable strategy for breast cancer treatment. In this study, we report the anti-tumor activity of a hydroxamate-based histone deacetylase (HDAC)8-selective inhibitor, HMC, in breast cancer cells. MTT assays showed that HMC inhibited cell viability of MCF-7 and MDA-MB-231 cells with IC<sub>50</sub> values of 7.7 μM and 9.5 μM, respectively. HMC induced caspase-dependent apoptosis in MCF-7 cells, which was associated with its ability to modulate a series of cell survival-related signaling effectors, including Akt, mTOR, Bax, Mcl-1, and Bcl-2. Additionally, HMC was capable of activating PPARγ, which was accompanied by reduced expression of PPARγ target gene products, such as cyclin D1 and CDK6. HMC increased the production of ROS in MCF-7 cells, which could be partially reversed by the cotreatment with a ROS scavenger (<italic>N</italic>-acetylcysteine or glutathione). Furthermore, HMC induced autophagy, as characterized by the formation of acidic vesicular organelles and autophagic biomarkers including LC3B-II and Atg5. Notably, pharmacological blockade of autophagy by 3-MA or CQ could attenuate HMC-induced apoptosis, suggesting that autophagy played a self-protective role in HMC-induced cell death. Together, these data suggest the translational potential of HMC to be developed into a potential therapeutic agent for breast cancer therapy.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Bray, F" uniqKey="Bray F">F. Bray</name></author><author><name sortKey="Ferlay, J" uniqKey="Ferlay J">J. Ferlay</name></author><author><name sortKey="Soerjomataram, I" uniqKey="Soerjomataram I">I. Soerjomataram</name></author><author><name sortKey="Siegel, R L" uniqKey="Siegel R">R.L. Siegel</name></author><author><name sortKey="Torre, L A" uniqKey="Torre L">L.A. Torre</name></author><author><name sortKey="Jemal, A" uniqKey="Jemal A">A. Jemal</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ziegler, R G" uniqKey="Ziegler R">R.G. 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Liu</name></author><author><name sortKey="Hsiao, Y T" uniqKey="Hsiao Y">Y.T. Hsiao</name></author><author><name sortKey="Feng, C H" uniqKey="Feng C">C.H. Feng</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hsiao, Y C" uniqKey="Hsiao Y">Y.C. Hsiao</name></author><author><name sortKey="Peng, S F" uniqKey="Peng S">S.F. Peng</name></author><author><name sortKey="Lai, K C" uniqKey="Lai K">K.C. Lai</name></author><author><name sortKey="Liao, C L" uniqKey="Liao C">C.L. Liao</name></author><author><name sortKey="Huang, Y P" uniqKey="Huang Y">Y.P. Huang</name></author><author><name sortKey="Lin, C C" uniqKey="Lin C">C.C. Lin</name></author><author><name sortKey="Lin, M L" uniqKey="Lin M">M.L. Lin</name></author><author><name sortKey="Liu, K C" uniqKey="Liu K">K.C. Liu</name></author><author><name sortKey="Tsai, C C" uniqKey="Tsai C">C.C. Tsai</name></author><author><name sortKey="Ma, Y S" uniqKey="Ma Y">Y.S. Ma</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Weng, J R" uniqKey="Weng J">J.R. Weng</name></author><author><name sortKey="Bai, L Y" uniqKey="Bai L">L.Y. Bai</name></author><author><name sortKey="Chiu, S J" uniqKey="Chiu S">S.J. Chiu</name></author><author><name sortKey="Chiu, C F" uniqKey="Chiu C">C.F. Chiu</name></author><author><name sortKey="Lin, W Y" uniqKey="Lin W">W.Y. Lin</name></author><author><name sortKey="Hu, J L" uniqKey="Hu J">J.L. Hu</name></author><author><name sortKey="Shieh, T M" uniqKey="Shieh T">T.M. Shieh</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Taïwan</li></country></list><tree><noCountry><name sortKey="Huang, Wei Jan" sort="Huang, Wei Jan" uniqKey="Huang W" first="Wei-Jan" last="Huang">Wei-Jan Huang</name></noCountry><country name="Taïwan"><noRegion><name sortKey="Chiu, Chang Fang" sort="Chiu, Chang Fang" uniqKey="Chiu C" first="Chang-Fang" last="Chiu">Chang-Fang Chiu</name></noRegion><name sortKey="Bai, Li Yuan" sort="Bai, Li Yuan" uniqKey="Bai L" first="Li-Yuan" last="Bai">Li-Yuan Bai</name><name sortKey="Chin, Hsien Kuo" sort="Chin, Hsien Kuo" uniqKey="Chin H" first="Hsien-Kuo" last="Chin">Hsien-Kuo Chin</name><name sortKey="Chiu, Chang Fang" sort="Chiu, Chang Fang" uniqKey="Chiu C" first="Chang-Fang" last="Chiu">Chang-Fang Chiu</name><name sortKey="Huang, Hao Yu" sort="Huang, Hao Yu" uniqKey="Huang H" first="Hao-Yu" last="Huang">Hao-Yu Huang</name><name sortKey="Weng, Jing Ru" sort="Weng, Jing Ru" uniqKey="Weng J" first="Jing-Ru" last="Weng">Jing-Ru Weng</name><name sortKey="Weng, Jing Ru" sort="Weng, Jing Ru" uniqKey="Weng J" first="Jing-Ru" last="Weng">Jing-Ru Weng</name><name sortKey="Weng, Jing Ru" sort="Weng, Jing Ru" uniqKey="Weng J" first="Jing-Ru" last="Weng">Jing-Ru Weng</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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