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

Molecular Cancer

Research

Ping Yue¹  Baoxiang Guan¹  Shi-Yong Sun¹  Junghui Koo¹  Fadlo R Khuri¹  Xingming Deng²  Mingwei Chen³  Hui Ren⁴ 

[1] Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia, USA;Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia, USA;Department of Respiration, First Affiliated Hospital of Medical College of Xi’an Jiaotong University, Xi’anShaanxi, P R China;Department of Respiration, First Affiliated Hospital of Medical College of Xi’an Jiaotong University, Xi’anShaanxi, P R China;Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia, USA;

关键词: API-1;    GSK3;    Mcl-1;    E3 ubiquitin ligase;    Apoptosis;    Lung cancer;   

DOI  :  10.1186/1476-4598-12-146

 received in 2013-08-29, accepted in 2013-11-18,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundThe novel Akt inhibitor, API-1, induces apoptosis through undefined mechanisms. The current study focuses on revealing the mechanisms by which API-1 induces apoptosis.ResultsAPI-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.ConclusionsAPI-1 induces GSK3-dependent, β-TrCP- and FBXW7-mediated Mcl-1 degradation, resulting in induction of apoptosis.

【 授权许可】

Unknown   
© Ren et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.