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. 2014 Mar 26;5(9):2372–2389. doi: 10.18632/oncotarget.1706

Figure 4. NVP-AUY922 induced ER stress and mitochondrial damage, which was fueled by oxidative stress when combined with NVP-BEZ235.

Figure 4

(A) CCA cells were incubated with 0.5 uM NVP-AUY922 for 0, 2, 4, 8, 16, and 24 h. Whole cell lysates were subjected to western blot analysis for HSP70, Grp94, Grp78, p-eIF2α, CHOP, IRE1α, and phosphor-JNK. β-Actin was used as the loading control; (B) CCA cells were incubated with 0.5 uM NVP-AUY922 for 48 h. The red and green color ratio of JC-1 reflects the change in the mitochondrial membrane potential (ΔΨm); (C) Relative levels of reduced glutathione (GSH) in CGCCA cell line treated with 0.5 uM NVP-AUY922 and NVP-BEZ235 alone or combined for 0, 24, and 48 h. (D) Reactive oxidative species (ROS) levels induced by 0.5 uM NVP-AUY922 and NVP-BEZ235 alone or combined for 0, 18, and 24 h in CGCCA cell line. (E) The model shows that NVP-AUY922 induces ER stress, which leads to mitochondrial damage, and ultimately to apoptosis. When combined with NVP-BEZ235 treatment, this process is fueled by oxidative stress. NVP-BEZ235 and NVP-AUY922 cooperate to induce apoptosis by vertically affecting the PI3K/Akt/mTOR signaling pathway at multiple nodes.