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Article: Combination of proteasome and class I HDAC inhibitors induces apoptosis of NPC cells through an HDAC6-independent ER stress-induced mechanism

TitleCombination of proteasome and class I HDAC inhibitors induces apoptosis of NPC cells through an HDAC6-independent ER stress-induced mechanism
Authors
Issue Date2014
Citation
International Journal of Cancer, 2014, v. 135 n. 12, p. 2950-2961 How to Cite?
AbstractThe current paradigm stipulates that inhibition of histone deacetylase (HDAC) 6 is essential for the combinatorial effect of proteasome and HDAC inhibitors for the treatment of cancers. Our study aims to investigate the effect of combining different class I HDAC inhibitors (without HDAC6 action) with a proteasome inhibitor on apoptosis of nasopharyngeal carcinoma (NPC). We found that combination of a proteasome inhibitor, bortezomib, and several class I HDAC inhibitors, including MS-275, apicidin and romidepsin, potently induced killing of NPC cells both in vitro and in vivo. Among the drug pairs, combination of bortezomib and romidepsin (bort/romidepsin) was the most potent and could induce apoptosis at low nanomolar concentrations. The apoptosis of NPC cells was reactive oxygen species (ROS)- and caspase-dependent but was independent of HDAC6 inhibition. Of note, bort/romidepsin might directly suppress the formation of aggresome through the downregulation of c-myc. In addition, two markers of endoplasmic reticulum (ER) stress-induced apoptosis, ATF-4 and CHOP/GADD153, were upregulated, whereas a specific inhibitor of caspase-4 (an initiator of ER stress-induced apoptosis) could suppress the apoptosis. When ROS level in the NPC cells was reduced to the untreated level, ER stress-induced caspase activation was abrogated. Collectively, our data demonstrate a model of synergism between proteasome and class I HDAC inhibitors in the induction of ROS-dependent ER stress-induced apoptosis of NPC cells, independent of HDAC6 inhibition, and provide the rationale to combine the more specific and potent class I HDAC inhibitors with proteasome inhibitors for the treatment of cancers.
Persistent Identifierhttp://hdl.handle.net/10722/198062

 

DC FieldValueLanguage
dc.contributor.authorHui, KFen_US
dc.contributor.authorChiang, AKSen_US
dc.date.accessioned2014-06-25T02:43:48Z-
dc.date.available2014-06-25T02:43:48Z-
dc.date.issued2014en_US
dc.identifier.citationInternational Journal of Cancer, 2014, v. 135 n. 12, p. 2950-2961en_US
dc.identifier.urihttp://hdl.handle.net/10722/198062-
dc.description.abstractThe current paradigm stipulates that inhibition of histone deacetylase (HDAC) 6 is essential for the combinatorial effect of proteasome and HDAC inhibitors for the treatment of cancers. Our study aims to investigate the effect of combining different class I HDAC inhibitors (without HDAC6 action) with a proteasome inhibitor on apoptosis of nasopharyngeal carcinoma (NPC). We found that combination of a proteasome inhibitor, bortezomib, and several class I HDAC inhibitors, including MS-275, apicidin and romidepsin, potently induced killing of NPC cells both in vitro and in vivo. Among the drug pairs, combination of bortezomib and romidepsin (bort/romidepsin) was the most potent and could induce apoptosis at low nanomolar concentrations. The apoptosis of NPC cells was reactive oxygen species (ROS)- and caspase-dependent but was independent of HDAC6 inhibition. Of note, bort/romidepsin might directly suppress the formation of aggresome through the downregulation of c-myc. In addition, two markers of endoplasmic reticulum (ER) stress-induced apoptosis, ATF-4 and CHOP/GADD153, were upregulated, whereas a specific inhibitor of caspase-4 (an initiator of ER stress-induced apoptosis) could suppress the apoptosis. When ROS level in the NPC cells was reduced to the untreated level, ER stress-induced caspase activation was abrogated. Collectively, our data demonstrate a model of synergism between proteasome and class I HDAC inhibitors in the induction of ROS-dependent ER stress-induced apoptosis of NPC cells, independent of HDAC6 inhibition, and provide the rationale to combine the more specific and potent class I HDAC inhibitors with proteasome inhibitors for the treatment of cancers.en_US
dc.languageengen_US
dc.relation.ispartofInternational Journal of Canceren_US
dc.subject.meshApoptosis-
dc.subject.meshEndoplasmic Reticulum Stress-
dc.subject.meshHistone Deacetylase Inhibitors - chemistry-
dc.subject.meshHistone Deacetylases - metabolism-
dc.subject.meshNasopharyngeal Neoplasms - metabolism-
dc.subject.meshProteasome Endopeptidase Complex - chemistry-
dc.titleCombination of proteasome and class I HDAC inhibitors induces apoptosis of NPC cells through an HDAC6-independent ER stress-induced mechanismen_US
dc.typeArticleen_US
dc.identifier.emailHui, KF: kfhui@hku.hken_US
dc.identifier.emailChiang, AKS: chiangak@hku.hken_US
dc.identifier.authorityChiang, AKS=rp00403en_US
dc.identifier.doi10.1002/ijc.28924en_US
dc.identifier.pmid24771510-
dc.identifier.hkuros229248en_US

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