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: Guangbo Liu, Ling Su, Xuexi Hao, Ning Zhong, Diansheng Zhong, Sunil Singhal, Xiangguo Liu
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 16 Issue 7 Pg. 1618-28 (Jul 2012) ISSN: 1582-4934 [Electronic] England
• PMID: 21801305 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Chemical References

• ATF3 protein, human
• ATF4 protein, human
• Activating Transcription Factor 3
• DDIT3 protein, human
• Histone Deacetylase Inhibitors
• N-(3-((2-hydroxynaphthalen-1-ylmethylene)amino)phenyl)-2-phenylpropionamide
• Naphthols
• Phenylpropionates
• RNA, Small Interfering
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Activating Transcription Factor 4
• Transcription Factor CHOP
• Poly(ADP-ribose) Polymerases
• CASP3 protein, human
• CASP8 protein, human
• CASP9 protein, human
• Caspase 3
• Caspase 8
• Caspase 9
• SIRT1 protein, human
• SIRT2 protein, human
• Sirtuin 1
• Sirtuin 2

Topics

• Activating Transcription Factor 3 (genetics, metabolism)
• Activating Transcription Factor 4 (genetics, metabolism)
• Apoptosis (drug effects)
• Caspase 3
• Caspase 8 (genetics, metabolism)
• Caspase 9 (genetics, metabolism)
• Cell Line, Tumor
• Endoplasmic Reticulum (drug effects, genetics, metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Knockdown Techniques
• Gene Silencing
• Histone Deacetylase Inhibitors (metabolism)
• Humans
• Lung Neoplasms (genetics)
• Naphthols (pharmacology)
• Phenylpropionates (pharmacology)
• Poly(ADP-ribose) Polymerases (genetics, metabolism)
• RNA, Small Interfering (metabolism)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (genetics, metabolism)
• Signal Transduction
• Sirtuin 1 (genetics, metabolism)
• Sirtuin 2 (genetics, metabolism)
• Transcription Factor CHOP (genetics, metabolism)
• Up-Regulation