Salermide up‐regulates death receptor 5 expression through the ATF4‐ATF3‐CHOP axis and leads to apoptosis in human cancer cells

Journal of Cellular and Molecular Medicine

Guangbo Liu⁵  Ling Su⁵  Xuexi Hao¹  Ning Zhong²  Diansheng Zhong⁴  Sunil Singhal³ 

[1] The Second Hospital, Shandong University, Jinan, China;School of Medicine, Shandong University, Jinan, China;Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA, USA;Tianjin Key Laboratory of Lung Cancer Metastasis and Tumour Environment, Tianjin Medical University General Hospital, Tianjin, China;School of Life Sciences, Shandong University, Jinan, China

关键词: salermide;    death receptor 5 (DR5);    ATF3;    ATF4;    CHOP;    endoplasmic reticulum (ER) stress;    Sirt1/2;   

DOI  :  10.1111/j.1582-4934.2011.01401.x

来源: Wiley

【 摘 要 】

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.

【 授权许可】

Unknown   
© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd