title: Involvement of general control nonderepressible kinase 2 in cancer cell apoptosis by posttranslational mechanisms.
abstract: 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.
authors.affiliation: State Key Lab of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing 210093, China State Key Lab of Natural Medicines, China Pharmaceutical University, Nanjing 210017, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wei
authors.affiliation: State Key Lab of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Ma
authors.initials: M
authors.lastname: Lin
authors.affiliation: Department of Anaesthesiology and Intensive Care Unit, Changhai Hospital, Affiliated Hospital of the Second Military Medical University, Shanghai 200433, China.
authors.forename: Bian
authors.initials: B
authors.lastname: Jinjun
authors.affiliation: State Key Lab of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Su
authors.affiliation: State Key Lab of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Cao
authors.initials: C
authors.lastname: Dan
authors.affiliation: Department of Chinese Medicine, Jiangsu Cancer Hospital, Nanjing 210009, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Yan
authors.affiliation: State Key Lab of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Jie
authors.affiliation: State Key Lab of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Jin
authors.affiliation: State Key Lab of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing 210093, China State Key Lab of Natural Medicines, China Pharmaceutical University, Nanjing 210017, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Zi-Chun
authors.affiliation: State Key Lab of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing 210093, China State Key Lab of Natural Medicines, China Pharmaceutical University, Nanjing 210017, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Wu
mesh_terms: D017209:Apoptosis; D019390:Arrestins / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D015870:Gene Expression; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D000075702:Nedd4 Ubiquitin Protein Ligases; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D059748:Proteolysis; D051742:Transcription Factor CHOP / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; C497249:DDIT3 protein, human; D056827:Endosomal Sorting Complexes Required for Transport; D000071557:beta-Arrestins; D051742:Transcription Factor CHOP; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618485:Nedd4L protein, human; D044767:Ubiquitin-Protein Ligases; C529271:EIF2AK4 protein, human; D017346:Protein Serine-Threonine Kinases