FIGURE 8.

ATF4 stabilisation by BTZ or CK1δ inhibitor enhances the efficacy of chemotherapy in gastric cancer. Viability (A) and apoptosis (B) of SGC7901 cells treated by DDP with/without BTZ (0.1μM) for 24 h was measured. (C) Viability of SGC7901 cells treated by DDP and D4476 (0, 12.5 or 25 μM) for 24 h was measured by MTS assay. (D) Apoptosis of BGC823 cells treated by DDP and D4476 (25μM) for 24 h was measured. Xenograft model was performed with SGC7901 cells under indicated treatments, tumour growth curve (E) was plotted according to the tumour volume measured every other day, tumour weight (F) and tumour photos (G) were obtained at the end of the experiment. (H) Expression of ATF4, CHOP and Ki67 in different groups as indicated were analysed by IHC. (I) Proposed model. Generally, chemotherapeutics could promote ATF4 to activate CHOP transcription, thus inducing cell apoptosis. Simultaneously, chemotherapeutics increases ATF4‐S219 phosphorylation via CK1δ, which subsequently enhances βTrCP‐mediated ATF4 poly‐ubiquitination‐dependent proteasomal degradation, eventually resulting in chemoresistance. Therefore, this acquired resistance is a dynamic reversible process. Upon drug withdraw, ATF4 expression gradually recovers and resistant cells will re‐sensitise to chemotherapeutics