Fig. 5: Metabolic synthetic lethality induced by LDHB/SLC7A11 inhibition converges on glutamine metabolism.
From: Lactate dehydrogenase B noncanonically promotes ferroptosis defense in KRAS-driven lung cancer
a Volcano plot showing the metabolomics profile of A549 cells transfected for 48 h with siLDHB or siNT and further treated with erastin (5 µM) or vehicle for 20 h. b The metabolic pathways most significantly upregulated in erastin-treated LDHB KD cells compared to those in vehicle-treated control cells. c Schematic of glutamine metabolism and glutamine-fueled glutaminolysis. Inhibitors that mitigate LDHB/SLC7A11 inhibition-induced ferroptosis are highlighted in green. d, e Oxygen consumption rate (OCR) measurement d and quantification e of A549 cells transfected with siLDHB or siNT for 48 h and further treated for 20 h with DMSO or erastin (5 μM). Cell numbers normalized to 50 ng/DNA. Data represent the average of basal respiration, maximal respiration, and ATP production taken at multiple time points during the respective phases of the Seahorse assay, and are shown as mean ± s.e.m (n = 6). f, g, OCR measure f and quantification g of A549 KD cells transfected with siLDHB or siNT for 48 h and further treated for 20 h with DMSO, erastin (5 μM), CB839 (0.5 μM), BPTES (2 μM), and GPNA (50 μM), alone or in combination. Normalization was based on vehicle-treated siNT and siLDHB groups (set as 100%), respectively. Data represent the average of basal respiration, maximal respiration, and ATP production taken at multiple time points during the respective phases of the Seahorse assay, and are shown as mean ± s.e.m (n = 6). h MitoSox (mitochondrial ROS marker) quantification (left) and flow cytometry (right) analysis of A549 cells transfected and treated as above d–g; MitoROS is shown as mean fluorescence intensity (MFI) ± s.d. (n = 3), with the siNT group used for normalization. i Viability assay of A549 cells transfected with siLDHB or siNT for 48 h and further treated for 20 h with DMSO, erastin (5 μM), CB839 (0.5 μM), BPTES (2 μM), and GPNA (50 μM), alone or in combination. Normalization was based on vehicle-treated siNT and siLDHB groups (set as 100%), respectively.
