The E3 ubiquitin ligases β-TrCP and FBXW7 cooperatively mediates GSK3-dependent Mcl-1 degradation induced by the Akt inhibitor API-1, resulting in apoptosis

• Type of Material: Article
• Authors: Hui Ren, Xi’an Jiaotong University; Junghui Koo, Emory University; Baoxiang Guan, Emory University; Ping Yue, Emory University; Xingming Deng, Emory University; Mingwei Chen, Xi’an Jiaotong University; Fadlo Khuri, Emory University; Shi-Yong Sun, Emory University
• Language: English
• Date: 2013
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2013 Ren et al.; licensee BioMed Central Ltd.
• License: Creative Commons Attribution 2.0 Generic
• Final Published Version (URL): http://www.molecular-cancer.com/content/12/1/146
• Title of Journal or Parent Work: Molecular Cancer
• ISSN: 1476-4598
• Volume: 12
• Issue: 146
• Grant/Funding Information: FR Khuri and S-Y Sun are Georgia Cancer Coalition Distinguished Cancer Scholars.; This study was supported by NIH R01 CA118450 (S-Y Sun) and R01 CA160522 (S-Y Sun).
• Keywords: Apoptosis; Mcl-1; E3 ubiquitin ligase,; Lung cance; GSK3; API-1
• Research Categories: Health Sciences, Oncology

Abstract

Background The novel Akt inhibitor, API-1, induces apoptosis through undefined mechanisms. The current study focuses on revealing the mechanisms by which API-1 induces apoptosis. Results API-1 rapidly and potently reduced the levels of Mcl-1 primarily in API-1-senstive lung cancer cell lines. Ectopic expression of Mcl-1 protected cells from induction of apoptosis by API-1. API-1 treatment decreased the half-life of Mcl-1, whereas inhibition of the proteasome with MG132 rescued Mcl-1 reduction induced by API-1. API-1 decreased Mcl-1 levels accompanied with a rapid increase in Mcl-1 phosphorylation (S159/T163). Moreover, inhibition of GSK3 inhibited Mcl-1 phosphorylation and reduction induced by API-1 and antagonized the effect of API-1 on induction of apoptosis. Knockdown of either FBXW7 or β-TrCP alone, both of which are E3 ubiquitin ligases involved in Mcl-1 degradation, only partially rescued Mcl-1 reduction induced by API-1. However, double knockdown of both E3 ubiquitin ligases enhanced the rescue of API-1-induced Mcl-1 reduction. Conclusions API-1 induces GSK3-dependent, β-TrCP- and FBXW7-mediated Mcl-1 degradation, resulting in induction of apoptosis.