title: Salermide up-regulates death receptor 5 expression through the ATF4-ATF3-CHOP axis and leads to apoptosis in human cancer cells.
abstract: Sirtuins (a class III histone deacetylase) have emerged as novel targets for cancer therapy. Salermide, a reverse amide compound that inhibits Sirtuin 1 (Sirt1) and Sirtuin 2 (Sirt2), has been shown to induce apoptosis in human cancer cells. The mechanism underlying cellular apoptotic signalling by salermide remains unclear. In this study, we show that salermide up-regulates the expression of death receptor 5 (DR5) in human non-small cell lung cancer (NSCLC) cells. Blocking DR5 expression by gene silencing technology results in a decrease in activated forms of several pro-apoptotic proteins (caspase-8, caspase-9, caspase-3, PARP). Increasing DR5 protein expression correlates with salermide-induced apoptosis in human NSCLC cells. We discovered that IRE-1α, Bip, activating transcription factor 3 (ATF4), activating transcription factor 3 (ATF3) and C/EBP homologous protein (CHOP) are induced by salermide, which suggests that DR5-dependent apoptosis is induced by endoplasmic reticulum stress. Moreover, knockdown of Sirt1 and Sirt2 expression resulted in up-regulation of ATF4, CHOP and DR5. Transfected NSCLC cells with ATF4, ATF3 or CHOP siRNA results in a decline in pro-apoptotic proteins (such as caspase-8, caspase-9, caspase-3 and PARP) despite salermide treatment. We demonstrate that salermide induces expression of ATF4, and ATF4 up-regulates ATF3 and subsequently modulates CHOP. This suggests that DR5 is modulated by the ATF4-ATF3-CHOP axis in NSCLC after Sirt1/2 inhibition or salermide treatment. This study highlights the importance of DR5 up-regulation in apoptosis induced by Sirt1/2 inhibition and elucidates the underlying mechanism in human NSCLC cells.
authors.affiliation: School of Life Sciences, Shandong University, Jinan, China.
authors.forename: Guangbo
authors.initials: G
authors.lastname: Liu
authors.forename: Ling
authors.initials: L
authors.lastname: Su
authors.forename: Xuexi
authors.initials: X
authors.lastname: Hao
authors.forename: Ning
authors.initials: N
authors.lastname: Zhong
authors.forename: Diansheng
authors.initials: D
authors.lastname: Zhong
authors.forename: Sunil
authors.initials: S
authors.lastname: Singhal
authors.forename: Xiangguo
authors.initials: X
authors.lastname: Liu
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism; D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D009284:Naphthols / Q000494:pharmacology*; D010666:Phenylpropionates / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D056565:Sirtuin 2 / Q000235:genetics / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C490449:ATF3 protein, human; C497109:ATF4 protein, human; D051700:Activating Transcription Factor 3; C497249:DDIT3 protein, human; D056572:Histone Deacetylase Inhibitors; C539427:N-(3-((2-hydroxynaphthalen-1-ylmethylene)amino)phenyl)-2-phenylpropionamide; D009284:Naphthols; D010666:Phenylpropionates; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; C447939:SIRT1 protein, human; C474199:SIRT2 protein, human; D056564:Sirtuin 1; D056565:Sirtuin 2