Involvement of general control nonderepressible kinase 2 in cancer cell apoptosis by posttranslational mechanisms

• Published in: Molecular biology of the cell 2015-03, Vol.26 (6), p.1044-1057
• Main Authors: Wei, Chen, Lin, Ma, Jinjun, Bian, Su, Feng, Dan, Cao, Yan, Chen, Jie, Yang, Jin, Zhang, Zi-Chun, Hua, Wu, Yin
• Format: Article
• Language: English
• Subjects: Apoptosis; Arrestins - metabolism; beta-Arrestins; Endosomal Sorting Complexes Required for Transport - metabolism; Gene Expression; HCT116 Cells; HT29 Cells; Humans; Nedd4 Ubiquitin Protein Ligases; Phosphorylation; Protein-Serine-Threonine Kinases - physiology; Proteolysis; Transcription Factor CHOP - metabolism; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 1059-1524; 1939-4586
• DOI: 10.1091/mbc.E14-10-1438

General control nonderepressible kinase 2 (GCN2) is a promising target for cancer therapy. However, the role of GCN2 in cancer cell survival or death is elusive; further, small molecules targeting GCN2 signaling are not available. By using a GCN2 level-based drug screening assay, we found that GCN2 protein level critically determined the sensitivity of the cancer cells toward Na(+),K(+)-ATPase ligand-induced apoptosis both in vitro and in vivo, and this effect was largely dependent on C/EBP homologous protein (CHOP) induction. Further analysis revealed that GCN2 is a short-lived protein. In A549 lung carcinoma cells, cellular β-arrestin1/2 associated with GCN2 and maintained the GCN2 protein level at a low level by recruiting the E3 ligase NEDD4L and facilitating consequent proteasomal degradation. However, Na(+),K(+)-ATPase ligand treatment triggered the phosphorylation of GCN2 at threonine 899, which increased the GCN2 protein level by disrupting the formation of GCN2-β-arrestin-NEDD4L ternary complex. The enhanced GCN2 level, in turn, aggravated Na(+),K(+)-ATPase ligand-induced cancer cell apoptosis. Our findings reveal that GCN2 can exert its proapoptotic function in cancer cell death by posttranslational mechanisms. Moreover, Na(+),K(+)-ATPase ligands emerge as the first identified small-molecule drugs that can trigger cancer cell death by modulating GCN2 signaling.