Skip to main content
. 2021 Aug 27;7(35):eabj0364. doi: 10.1126/sciadv.abj0364

Fig. 6. Cotargeting CAIX/XII and xCT blunts signaling through AMPK to enhance ferroptosis in a pH-dependent manner.

Fig. 6

(A and B) pHi measurements in hypoxic SUM159PT cells following the indicated treatments for 72 hours. (A) SLC-0111 (0, 25, 50, and 100 μM,), compound 11 (2 μM), and compound 13 (50 μM); (B) NT, untreated; S, S0859 (25 μM); N, NH4Cl (2.5 mM). Cell viability of hypoxic (C) SUM159PT and (D) LM2-4 treated with the indicated concentrations of S0859 and erastin for 72 hours. Cell viability of SUM159PT cells treated with SLC-0111 (50 μM) and erastin (0.5 μM) (E) or S0859 (50 μM) and erastin (F) in the presence of NH4Cl (1, 2.5, 5, and 10 mM) for 72 hours in hypoxia. Indicated protein levels of SUM159PT cells treated with (G) SLC-0111 (12.5 μM) and erastin (0.25 μM) or (H) S0859 (12.5 μM) and erastin (0.25 μM) for 72 hours in hypoxia. Cell viability data of SUM159PT treated with erastin and SLC-0111 (I) or S0859 (J) together with the indicated compounds for 72 hours in hypoxia. AICAR (0.25, 0.5, and 1.0 μM), TOFA (12.5, 25, and 50 μM), and rosiglitazone (ROSI; 1.0, 5.0, and 10 μM). Cell viability data of SUM159PT treated with siRNA to ACC1 together with SLC-0111 (K) or S0859 (L) and erastin for 72 hours in hypoxia. (M) Model depicting role of CAIX and sodium-driven bicarbonate cotransporters in pH homeostasis and suppression of ferroptosis. Bars indicate means ± SEM. Shown are representative experiments from experiments performed at least twice. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. Statistical significance was assessed using t test with Welch’s correction (F) or one-way (A, B, E, I, and J) or two-way ANOVA (C, D, K, and L) followed by Tukey’s multiple comparisons test post hoc.