Metformin Induces Apoptosis through AMPK-Dependent Inhibition of UPR Signaling in ALL Lymphoblasts
Figure 3
Inhibition of mTOR-dependent protein synthesis reverses metformin-induced cell death.
A) Apoptosis in CCRF-CEM cells expressing either scramble shRNA (shCTRL) or shRNA against AMPKα1 (shAMPK) treated with metformin (MET, 10 mM) for 48 h. B) Immunoblotting of AMPK, Akt/mTOR, and ER stress/UPR signaling pathway proteins in the cells described in (A). C) Cell death (upper panel) in CCRF-CEM and NALM6 cells treated with metformin (MET, 5 and 10 mM) and rapamycin (RAPA; 0.1 µg/mL), either alone or in combination for 48 h. A statistical value of p < 0.01 was obtained for MET + RAPA vs. either control or each agent alone. The cell death was expressed as a percentage (%) of cells in the population (mean ±SEM, n = 3). Western blot analysis (lower panel) of p-4EBP1 (T70), IRE1α, and CHOP expression in the CCRF-CEM and NALM6 cells treated with metformin plus rapamycin described in the upper panel.