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. 2021 Nov 5;7(45):eabg1964. doi: 10.1126/sciadv.abg1964

Fig. 4. l-Arginine suppression of tumor metabolism occurs in a NOS2-dependent manner.

Fig. 4.

(A) Extracellular lactate concentration in MDA-MB-231 and MDA-MB-231-BrM2 cells treated for 60 min with d-arginine (as control) or l-arginine at the indicated concentrations. (B and C) Principal components (PC) analyses of the metabolome of MDA-MB-231 and MDA-MB-468 cells treated in vitro with vehicle, NOS2 inhibitor 1400W, l-arginine, or their combination. (D and E) Sankey plots depicting statistically significant metabolic changes exerted by l-arginine alone or in combination with the NOS2 inhibitor 1400W in MDA-MB-231 and MDA-MB-468 cell lines. Data compared to vehicle. Selected metabolites are indicated. The color pattern of metabolites indicates similar changes. (F) Extracellular lactate concentration in a panel of TNBC and NSCLC cell lines exposed to l-arginine alone or in combination with the NOS2 inhibitor 1400W. (G) Oxygen consumption rate (OCR) in MDA-MB-231 cells exposed to vehicle (black), d-arginine (gray), or l-arginine (red) for the indicated times. FCCP, carbonyl cyanide p-trifluoromethoxyphenylhydrazone; OLIG, oligomycin; ROTN, rotenone. (H) Total cellular ATP levels (right x axis) and cell necrosis (left x axis) in MDA-MB-231 and MDA-MB-231-BrM2 cells treated with l-arginine for the indicated time points (y axis, in minutes). Cyclophosphamide was used as a positive control for cell necrosis (CTRL). (I) Total and phosphorylated levels of AMPK and its target ACC1 in MDA-MB-231 and MDA-MB-231-BrM2 cells treated with l-arginine for the indicated time points (in minutes). HSPA5 and actin were used as controls. *P < 0.01, **P < 0.001, and ***P < 0.0001.