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MPT0G612, a Novel HDAC6 Inhibitor, Induces Apoptosis and Suppresses IFN-γ-Induced Programmed Death-Ligand 1 in Human Colorectal Carcinoma Cells

Identifieur interne : 000B40 ( Ncbi/Merge ); précédent : 000B39; suivant : 000B41

MPT0G612, 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 :

RBID : PMC:6826904

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

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PMC:6826904

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<pmc article-type="research-article">
<pmc-dir>properties open_access</pmc-dir>
<front>
<journal-meta>
<journal-id journal-id-type="nlm-ta">Cancers (Basel)</journal-id>
<journal-id journal-id-type="iso-abbrev">Cancers (Basel)</journal-id>
<journal-id journal-id-type="publisher-id">cancers</journal-id>
<journal-title-group>
<journal-title>Cancers</journal-title>
</journal-title-group>
<issn pub-type="epub">2072-6694</issn>
<publisher>
<publisher-name>MDPI</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="pmid">31652644</article-id>
<article-id pub-id-type="pmc">6826904</article-id>
<article-id pub-id-type="doi">10.3390/cancers11101617</article-id>
<article-id pub-id-type="publisher-id">cancers-11-01617</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Article</subject>
</subj-group>
</article-categories>
<title-group>
<article-title>MPT0G612, a Novel HDAC6 Inhibitor, Induces Apoptosis and Suppresses IFN-γ-Induced Programmed Death-Ligand 1 in Human Colorectal Carcinoma Cells</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Chen</surname>
<given-names>Mei-Chuan</given-names>
</name>
<xref ref-type="aff" rid="af1-cancers-11-01617">1</xref>
<xref ref-type="aff" rid="af2-cancers-11-01617">2</xref>
<xref ref-type="author-notes" rid="fn1-cancers-11-01617"></xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Lin</surname>
<given-names>Yu-Chen</given-names>
</name>
<xref ref-type="aff" rid="af3-cancers-11-01617">3</xref>
<xref ref-type="author-notes" rid="fn1-cancers-11-01617"></xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Liao</surname>
<given-names>Yu-Hsuan</given-names>
</name>
<xref ref-type="aff" rid="af1-cancers-11-01617">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Liou</surname>
<given-names>Jing-Ping</given-names>
</name>
<xref ref-type="aff" rid="af4-cancers-11-01617">4</xref>
</contrib>
<contrib contrib-type="author">
<contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-6328-466X</contrib-id>
<name>
<surname>Chen</surname>
<given-names>Chun-Han</given-names>
</name>
<xref ref-type="aff" rid="af3-cancers-11-01617">3</xref>
<xref ref-type="aff" rid="af5-cancers-11-01617">5</xref>
<xref rid="c1-cancers-11-01617" ref-type="corresp">*</xref>
</contrib>
</contrib-group>
<aff id="af1-cancers-11-01617">
<label>1</label>
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.)</aff>
<aff id="af2-cancers-11-01617">
<label>2</label>
Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei 110, Taiwan</aff>
<aff id="af3-cancers-11-01617">
<label>3</label>
Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan;
<email>amylin0083@tmu.edu.tw</email>
</aff>
<aff id="af4-cancers-11-01617">
<label>4</label>
School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan;
<email>jpl@tmu.edu.tw</email>
</aff>
<aff id="af5-cancers-11-01617">
<label>5</label>
Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 110, Taiwan</aff>
<author-notes>
<corresp id="c1-cancers-11-01617">
<label>*</label>
Correspondence:
<email>brianchc@tmu.edu.tw</email>
; Tel.: +886-227-361-661 (ext. 3195)</corresp>
<fn id="fn1-cancers-11-01617">
<label></label>
<p>Mei-Chuan Chen and Yu-Chen Lin contribute equally to this work.</p>
</fn>
</author-notes>
<pub-date pub-type="epub">
<day>22</day>
<month>10</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="collection">
<month>10</month>
<year>2019</year>
</pub-date>
<volume>11</volume>
<issue>10</issue>
<elocation-id>1617</elocation-id>
<history>
<date date-type="received">
<day>27</day>
<month>9</month>
<year>2019</year>
</date>
<date date-type="accepted">
<day>18</day>
<month>10</month>
<year>2019</year>
</date>
</history>
<permissions>
<copyright-statement>© 2019 by the authors.</copyright-statement>
<copyright-year>2019</copyright-year>
<license license-type="open-access">
<license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (
<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
).</license-p>
</license>
</permissions>
<abstract>
<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>
</abstract>
<kwd-group>
<kwd>HDAC6</kwd>
<kwd>apoptosis</kwd>
<kwd>autophagy</kwd>
<kwd>PD-L1</kwd>
<kwd>colorectal cancer</kwd>
</kwd-group>
</article-meta>
</front>
<floats-group>
<fig id="cancers-11-01617-f001" orientation="portrait" position="float">
<label>Figure 1</label>
<caption>
<p>MPT0G612 inhibits cell proliferation and cell viability in CRC cells. MPT0G612 suppresses cell proliferative activity (
<bold>A</bold>
) and cell viability (
<bold>B</bold>
) in a concentration-dependent manner in HCT116, HT-29, and DLD-1 cells. The inhibitory effects of ACY-1215 and Tubastatin A on cell proliferation (
<bold>C</bold>
,
<bold>E</bold>
) and viability (
<bold>D</bold>
,
<bold>F</bold>
) in HCT116, HT-29, and DLD-1 cells. Cells were treated with or without the indicated concentrations of drugs for 48 h, and cell growth and cell viability were evaluated by SRB and MTT assay. Data are expressed as means ± S.D. of at least three independent experiments. *
<italic>p</italic>
< 0.05; **
<italic>p</italic>
< 0.01; and ***
<italic>p</italic>
< 0.001 compared with the control group.</p>
</caption>
<graphic xlink:href="cancers-11-01617-g001"></graphic>
</fig>
<fig id="cancers-11-01617-f002" orientation="portrait" position="float">
<label>Figure 2</label>
<caption>
<p>MPT0G612 induces subG1 cell accumulation and apoptosis in CRC cells. MPT0G612 enhances accumulation of subG1 phase in HCT116 (
<bold>A</bold>
) and HT-29 (
<bold>B</bold>
) cells. Cells were treated with indicated concentrations of MPT0G612 (G612) for 48 h, then the cell cycle distribution was analyzed by flow cytometry. Quantitative data are based on flow cytometry histograms, and presented as means ± S.D. of at least three independent experiments. *
<italic>p</italic>
< 0.05; **
<italic>p</italic>
< 0.01; and ***
<italic>p</italic>
< 0.001 compared with the control (CTL) group. MPT0G612 (G612) induces more significant apoptosis than ACY-1215 (ACY) and Tubastatin A (Tu) in CRC cells. HCT-116 (
<bold>C</bold>
) and HT-29 (
<bold>D</bold>
) cells were treated with the indicated concentrations of compounds for 48 h, and cell lysates were immunoblotted using the indicated antibodies. (
<bold>E</bold>
,
<bold>F</bold>
) MPT0G612 induces subG1 cell accumulation and apoptosis in a time-dependent manner. (E) HCT116 cells were treated with MPT0G612 (G612; 10 μM) for indicated times, then the cell cycle distribution was analyzed by flow cytometry. Quantitative data are based on flow cytometry histograms, and presented as means of at least three independent experiments. (F) MPT0G612 time-dependently induced apoptotic cell death. HCT116 cells were treated with MPT0G612 (G612; 10 μM) for indicated times, and subjected to immunoblotted using the indicated antibodies.</p>
</caption>
<graphic xlink:href="cancers-11-01617-g002"></graphic>
</fig>
<fig id="cancers-11-01617-f003" orientation="portrait" position="float">
<label>Figure 3</label>
<caption>
<p>MPT0G612 induces autophagy in a concentration-and time-dependent manner in CRC cells. HCT116 (
<bold>A</bold>
) and HT-29 (
<bold>B</bold>
) cells were exposed to indicated concentrations of MPT0G612, ACY-1215 (ACY) or Tubastatin (Tu) for 6 h. The cell lysates were subjected to western blot analysis. (
<bold>C</bold>
) The cells were treated with MPT0G612 (10 μM) for indicated times, and subjected to western blot analysis.</p>
</caption>
<graphic xlink:href="cancers-11-01617-g003"></graphic>
</fig>
<fig id="cancers-11-01617-f004" orientation="portrait" position="float">
<label>Figure 4</label>
<caption>
<p>MPT0G612 induces pro-survival autophagy in HCT116 cells. (
<bold>A</bold>
) Blockade of autophagy augments MPT0G612-induced apoptosis. The cells were treated with MPT0G612 (G612) in the presence or absence of chloroquine (CQ) for 48 h, and protein lysates were analyzed by western blot analysis with indicated antibodies (left panel). Cell viability was determined by MTT assay, and the data were presented as means ± S.D. of at least three independent experiments (right panel). *
<italic>p</italic>
< 0.05; **
<italic>p</italic>
< 0.01; and ***
<italic>p</italic>
< 0.001 compared with MPT0G612 treatment alone. (
<bold>B</bold>
) Knockdown of Atg5 potentiated MPT0G612-induced apoptosis. The cells were transduced with control vector (pLKO) or shRNA against Atg5 (Atg5KD) by lentivirus, and stable cells were obtained by puromycin selection (2 μg/mL). The cells were then treated with vehicle (C), MPT0G612 (G, 10 μM) or ACY-1215 (A, 10 μM) for 48 h, and subjected to western blot analysis by using indicated antibodies.</p>
</caption>
<graphic xlink:href="cancers-11-01617-g004"></graphic>
</fig>
<fig id="cancers-11-01617-f005" orientation="portrait" position="float">
<label>Figure 5</label>
<caption>
<p>HDAC6 plays a regulatory role in induction of apoptosis and autophagy. (
<bold>A</bold>
) Knockdown of HDAC6 augments apoptosis induced by MPT0G612 or ACY-1215 in HCT116 cells. The cells were transduced with control vector (pLKO) or shRNA against HDAC6 (HDAC6 KD) by lentivirus, and stable cells were obtained by puromycin selection (2 μg/mL). The cells were exposed to indicated concentrations of MPT0G612 (left panel) or ACY-1215 (right panel) for 48 h and subjected to western blotting. (
<bold>B</bold>
) Knockdown of HDAC6 rescues autophagy induced by MPT0G612 or ACY-1215 in HCT 116 cells. The cells stalely express control vector (pLKO) or shRNA against HDAC6 were treated with indicated concentrations of MPT0G612 (left panel) or ACY-1215 (right panel) for 48 h and subjected to western blotting.</p>
</caption>
<graphic xlink:href="cancers-11-01617-g005"></graphic>
</fig>
<fig id="cancers-11-01617-f006" orientation="portrait" position="float">
<label>Figure 6</label>
<caption>
<p>MPT0G612 inhibits IFN-γ-induced PD-L1 expression in CRC cells. MPT0G612 (
<bold>A</bold>
,
<bold>B</bold>
) and ACY-1215 (
<bold>C</bold>
) abrogated IFN-γ-induced PD-L1 levels in HCT116 or HT-29 cells. The cells were treated with indicated concentrations of compounds in the presence or absence of IFN-γ (10 ng/mL) for 48 h, and subjected to western blot analysis. (
<bold>D</bold>
) HCT116 cells stalely express control vector (pLKO) or shRNA against HDAC6 were treated with MPT0G612 (G612) or ACY-1215 (ACY) in the presence or absence of IFN-γ (10 ng/mL) for 48 h, and protein levels of PD-L1 was examined by western blotting.</p>
</caption>
<graphic xlink:href="cancers-11-01617-g006"></graphic>
</fig>
</floats-group>
</pmc>
<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>

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