MPT0G612, a Novel HDAC6 Inhibitor, Induces Apoptosis and Suppresses IFN-γ-Induced Programmed Death-Ligand 1 in Human Colorectal Carcinoma Cells
Identifieur interne : 000665 ( Main/Exploration ); précédent : 000664; suivant : 000666MPT0G612, a Novel HDAC6 Inhibitor, Induces Apoptosis and Suppresses IFN-γ-Induced Programmed Death-Ligand 1 in Human Colorectal Carcinoma Cells
Auteurs : Mei-Chuan Chen [Taïwan] ; Yu-Chen Lin ; Yu-Hsuan Liao ; Jing-Ping Liou ; Chun-Han Chen [Taïwan]Source :
- Cancers [ 2072-6694 ] ; 2019.
Abstract
Colorectal cancer (CRC) is the third most common cancer and the leading cause of cancer-associated death worldwide. Histone deacetylases (HDACs) have been implicated in regulating complex cellular mechanisms to influence tumor biology and immunogenicity in various types of cancer. The potential of selective inhibition of HDAC6 has been widely discussed for the treatment of hematologic malignancies. We previously identified that MPT0G612 is a novel HDAC6 inhibitor exhibiting a promising antitumor activity against several solid tumors. The purpose of the present study was to evaluate the feasibility and pharmacological mechanisms of MPT0G612 as a potential therapy for CRC patients. Results revealed that MPT0G612 significantly suppresses the proliferation and viability, as well as induces apoptosis in CRC cells. Autophagy activation with LC3B-II formation and p62 degradation was observed, and the inhibition of autophagy by pharmacological inhibitor or Atg5 knockdown enhances MPT0G612-induced cell death. In addition, HDAC6 knockdown reduces MPT0G612-mediated autophagy and further potentiates apoptotic cell death. Furthermore, MPT0G612 downregulates the expression of PD-L1 induced by IFN-γ in CRC cells. These results suggest that MPT0G612 is a potent cell death inducer through inhibiting HDAC6-associated pathway, and a potential agent for combination strategy with immune checkpoint inhibitors for the treatment of CRC.
Url:
DOI: 10.3390/cancers11101617
PubMed: 31652644
PubMed Central: 6826904
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">MPT0G612, a Novel HDAC6 Inhibitor, Induces Apoptosis and Suppresses IFN-γ-Induced Programmed Death-Ligand 1 in Human Colorectal Carcinoma Cells</title><author><name sortKey="Chen, Mei Chuan" sort="Chen, Mei Chuan" uniqKey="Chen M" first="Mei-Chuan" last="Chen">Mei-Chuan Chen</name><affiliation><nlm:aff id="af1-cancers-11-01617">Ph.D. Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan;<email>mcchen1250@tmu.edu.tw</email> (M.-C.C.);<email>a0916143813@gmail.com</email> (Y.-H.L.)</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af2-cancers-11-01617">Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei 110, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei 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Liou</name><affiliation><nlm:aff id="af4-cancers-11-01617">School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan;<email>jpl@tmu.edu.tw</email></nlm:aff></affiliation></author><author><name sortKey="Chen, Chun Han" sort="Chen, Chun Han" uniqKey="Chen C" first="Chun-Han" last="Chen">Chun-Han Chen</name><affiliation><nlm:aff id="af3-cancers-11-01617">Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan;<email>amylin0083@tmu.edu.tw</email></nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af5-cancers-11-01617">Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 110, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 110</wicri:regionArea><wicri:noRegion>Taipei 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type="wicri:Area/Main/Curation">000665</idno><idno type="wicri:Area/Main/Exploration">000665</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">MPT0G612, a Novel HDAC6 Inhibitor, Induces Apoptosis and Suppresses IFN-γ-Induced Programmed Death-Ligand 1 in Human Colorectal Carcinoma Cells</title><author><name sortKey="Chen, Mei Chuan" sort="Chen, Mei Chuan" uniqKey="Chen M" first="Mei-Chuan" last="Chen">Mei-Chuan Chen</name><affiliation><nlm:aff id="af1-cancers-11-01617">Ph.D. Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan;<email>mcchen1250@tmu.edu.tw</email> (M.-C.C.);<email>a0916143813@gmail.com</email> (Y.-H.L.)</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af2-cancers-11-01617">Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei 110, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei 110</wicri:regionArea><wicri:noRegion>Taipei 110</wicri:noRegion></affiliation></author><author><name sortKey="Lin, Yu Chen" sort="Lin, Yu Chen" uniqKey="Lin Y" first="Yu-Chen" last="Lin">Yu-Chen Lin</name><affiliation><nlm:aff id="af3-cancers-11-01617">Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan;<email>amylin0083@tmu.edu.tw</email></nlm:aff></affiliation></author><author><name sortKey="Liao, Yu Hsuan" sort="Liao, Yu Hsuan" uniqKey="Liao Y" first="Yu-Hsuan" last="Liao">Yu-Hsuan Liao</name><affiliation><nlm:aff id="af1-cancers-11-01617">Ph.D. Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan;<email>mcchen1250@tmu.edu.tw</email> (M.-C.C.);<email>a0916143813@gmail.com</email> (Y.-H.L.)</nlm:aff></affiliation></author><author><name sortKey="Liou, Jing Ping" sort="Liou, Jing Ping" uniqKey="Liou J" first="Jing-Ping" last="Liou">Jing-Ping Liou</name><affiliation><nlm:aff id="af4-cancers-11-01617">School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan;<email>jpl@tmu.edu.tw</email></nlm:aff></affiliation></author><author><name sortKey="Chen, Chun Han" sort="Chen, Chun Han" uniqKey="Chen C" first="Chun-Han" last="Chen">Chun-Han Chen</name><affiliation><nlm:aff id="af3-cancers-11-01617">Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan;<email>amylin0083@tmu.edu.tw</email></nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af5-cancers-11-01617">Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 110, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 110</wicri:regionArea><wicri:noRegion>Taipei 110</wicri:noRegion></affiliation></author></analytic><series><title level="j">Cancers</title><idno type="eISSN">2072-6694</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>Colorectal cancer (CRC) is the third most common cancer and the leading cause of cancer-associated death worldwide. Histone deacetylases (HDACs) have been implicated in regulating complex cellular mechanisms to influence tumor biology and immunogenicity in various types of cancer. The potential of selective inhibition of HDAC6 has been widely discussed for the treatment of hematologic malignancies. We previously identified that MPT0G612 is a novel HDAC6 inhibitor exhibiting a promising antitumor activity against several solid tumors. The purpose of the present study was to evaluate the feasibility and pharmacological mechanisms of MPT0G612 as a potential therapy for CRC patients. Results revealed that MPT0G612 significantly suppresses the proliferation and viability, as well as induces apoptosis in CRC cells. Autophagy activation with LC3B-II formation and p62 degradation was observed, and the inhibition of autophagy by pharmacological inhibitor or Atg5 knockdown enhances MPT0G612-induced cell death. In addition, HDAC6 knockdown reduces MPT0G612-mediated autophagy and further potentiates apoptotic cell death. Furthermore, MPT0G612 downregulates the expression of PD-L1 induced by IFN-γ in CRC cells. These results suggest that MPT0G612 is a potent cell death inducer through inhibiting HDAC6-associated pathway, and a potential agent for combination strategy with immune checkpoint inhibitors for the treatment of CRC.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Kelly, T K" uniqKey="Kelly T">T.K. Kelly</name></author><author><name sortKey="De Carvalho, D D" uniqKey="De Carvalho D">D.D. De Carvalho</name></author><author><name sortKey="Jones, P A" uniqKey="Jones P">P.A. Jones</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Timp, W" uniqKey="Timp W">W. Timp</name></author><author><name sortKey="Feinberg, A P" uniqKey="Feinberg A">A.P. 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Liu</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Taïwan</li></country></list><tree><noCountry><name sortKey="Liao, Yu Hsuan" sort="Liao, Yu Hsuan" uniqKey="Liao Y" first="Yu-Hsuan" last="Liao">Yu-Hsuan Liao</name><name sortKey="Lin, Yu Chen" sort="Lin, Yu Chen" uniqKey="Lin Y" first="Yu-Chen" last="Lin">Yu-Chen Lin</name><name sortKey="Liou, Jing Ping" sort="Liou, Jing Ping" uniqKey="Liou J" first="Jing-Ping" last="Liou">Jing-Ping Liou</name></noCountry><country name="Taïwan"><noRegion><name sortKey="Chen, Mei Chuan" sort="Chen, Mei Chuan" uniqKey="Chen M" first="Mei-Chuan" last="Chen">Mei-Chuan Chen</name></noRegion><name sortKey="Chen, Chun Han" sort="Chen, Chun Han" uniqKey="Chen C" first="Chun-Han" last="Chen">Chun-Han Chen</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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