Fig. 5

Fig. 5 Pharmacologically inhibiting ALT provides direct support for tumor-liver alanine cycling (A) Schematic to illustrate the transformation of BCAA carbon to key intermediates in central carbon metabolism. (B) Fractional labeling, relative to serum [U-13C] BCAAs, of the central carbon intermediates ?-ketoglutarate, glutamate, malate, and fumarate in tumors treated with either vehicle (Veh) or ?-chloroalanine (ALTi). Data are normalized to the vehicle-treated group. Serum [U-13C] BCAAs was determined by averaging [U-13C] isoleucine, [U-13C] leucine, and [U-13C] valine. Values are mean ± SEM; n = 6?7 zebrafish per condition. Full labeling data are available in Data S5. (C) Relative pool sizes of central carbon metabolites from BRAF/p53 animals treated with either vehicle (Veh) or ?-chloroalanine (ALTi). Data are normalized to the vehicle-treated group. Values are mean ± SEM; n = 6?10 zebrafish per condition. Data are available in Data S5. (D) Relative change from baseline in tumor volume after 10 days of ?-chloroalanine (ALT inhibitor) treatment. Values are mean ± SEM; n = 9?10 tumors per condition. Tumor dimensions are included Data S5. (E) Representative image of tumor regression in a BRAF/p53 fish after 10 days of ?-chloroalanine treatment. Statistically significant differences were assessed by a two-tailed paired t test and annotated as follows: ?p < 0.05, ??p < 0.01, ???p < 0.001, ????p < 0.0001, or n.s. = not significant.