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

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Molecular Cancer

, 12:146

First Online: 22 November 2013Received: 29 August 2013Accepted: 18 November 2013DOI: 10.1186-1476-4598-12-146

Cite this article as: Ren, H., Koo, J., Guan, B. et al. Mol Cancer 2013 12: 146. doi:10.1186-1476-4598-12-146


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.

KeywordsAPI-1 GSK3 Mcl-1 E3 ubiquitin ligase Apoptosis Lung cancer AbbreviationsAPI-14-amino-5,8-dihydro-5-oxo-8-β-D-ribofuranosyl-pyrido2,3-dpyrimidine-6-carboxamide

TRAILTumor necrosis factor-related apoptosis-inducing ligand

NSCLCNon-small cell lung cancer

GSK3Glycogen synthase kinase 3

β-TrCPβ-Transducin repeats-containing protein

FBXW7F-box-WD repeat-containing protein 7


GAPDHGlyceraldehyde 3-phosphate dehydrogenase


SRBSulforhodamine B

CICombination index

siRNASmall interfering RNA


RT-PCRReverse transcription-PCR

SCFSKP1-cullin1-F-box protein.

Electronic supplementary materialThe online version of this article doi:10.1186-1476-4598-12-146 contains supplementary material, which is available to authorized users.

Hui Ren, Junghui Koo, Baoxiang Guan contributed equally to this work.

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Autor: Hui Ren - Junghui Koo - Baoxiang Guan - Ping Yue - Xingming Deng - Mingwei Chen - Fadlo R Khuri - Shi-Yong Sun



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