nsc-177223 and Carcinoma--Non-Small-Cell-Lung

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.. 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.. API-1 induces GSK3-dependent, β-TrCP- and FBXW7-mediated Mcl-1 degradation, resulting in induction of apoptosis.

Topics: Apoptosis; beta-Transducin Repeat-Containing Proteins; Carcinoma, Non-Small-Cell Lung; Cell Cycle Proteins; Cell Line, Tumor; F-Box Proteins; F-Box-WD Repeat-Containing Protein 7; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Glycogen Synthase Kinase 3; Heterocyclic Compounds, 3-Ring; Humans; Leupeptins; Myeloid Cell Leukemia Sequence 1 Protein; Nucleosides; Phosphorylation; Proteasome Endopeptidase Complex; Proto-Oncogene Proteins c-akt; Ubiquitin-Protein Ligases