RT Journal Article
SR Electronic
T1 GZD824 Inhibits GCN2 and Sensitizes Cancer Cells to Amino Acid Starvation Stress
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 669
OP 676
DO 10.1124/molpharm.120.000070
VO 98
IS 6
A1 Yu Kato
A1 Kazuhiro Kunimasa
A1 Mizuki Takahashi
A1 Ayaka Harada
A1 Ikuko Nagasawa
A1 Masanori Osawa
A1 Yoshikazu Sugimoto
A1 Akihiro Tomida
YR 2020
UL http://molpharm.aspetjournals.org/content/98/6/669.abstract
AB Eukaryotic initiation factor 2α (eIF2α) kinase general control nonderepressible 2 (GCN2) drives cellular adaptation to amino acid limitation by activating the integrated stress response that induces activating transcription factor 4 (ATF4). Here, we found that a multikinase inhibitor, GZD824, which we identified using a cell-based assay with ATF4 immunostaining, inhibited the GCN2 pathway in cancer cells. Indeed, GZD824 suppressed GCN2 activation, eIF2α phosphorylation, and ATF4 induction during amino acid starvation stress. However, at lower nonsuppressive concentrations, GZD824 paradoxically stimulated eIF2α phosphorylation and ATF4 expression in a GCN2-dependent manner under unstressed conditions. Such dual properties conceivably arose from a direct effect on GCN2, as also observed in a cell-free GCN2 kinase assay and shared by a selective GCN2 inhibitor. Consistent with the GCN2 pathway inhibition, GZD824 sensitized certain cancer cells to amino acid starvation stress similarly to ATF4 knockdown. These results establish GZD824 as a multikinase GCN2 inhibitor and may enhance its utility as a drug under development.SIGNIFICANCE STATEMENT GZD824, as a direct general control nonderepressible 2 (GCN2) inhibitor, suppresses activation of the integrated stress response during amino acid limitation, whereas it paradoxically stimulates this stress-signaling pathway at lower nonsuppressive concentrations. The pharmacological activity we identify herein will provide the basis for the use of GZD824 to elucidate the regulatory mechanisms of GCN2 and to evaluate the potential of the GCN2–activating transcription factor 4 pathway as a target for cancer therapy.