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. 2018 Nov 22;104(5):1016–1025. doi: 10.3324/haematol.2018.204701

Figure 4.

Figure 4.

Inhibition of lipogenesis and cholesterogenesis enhances sensitivity to BH3 mimetics. (A) Scheme representing reductive carboxylation, lipogenesis and cholesterogenesis. (B) Apoptotic sensitivity of K562 resistant [E] cells exposed to A-1331852 (10 nM) for 4 h was restored following genetic knockdown for 72 h of key enzymes in fatty acid synthesis. Western blots confirmed the knockdown efficiency of the different short interfering (si) RNA. (C) Apoptotic sensitivity of K562 resistant [E] cells exposed to A-1331852 (10 nM) for 4 h was restored following pharmacological inhibition of key enzymes in fatty acid synthesis using SB204990 (1 μM) for 72 h or GSK2194069 (100 nM) for 48 h. (D) Metabolic supplementation of K562 sensitive [A] and resistant [E] cells with palmitate (50 μM) for 48 h prior to the exposure of cells to GSK2194069 (100 nM) overcame the sensitizing effect of GSK2194069 on A-1331852-mediated apoptosis. (E) Genetic knockdown for 72 h of HMGR or (F) pharmacological inhibition of HMGR by simvastatin (250 nM) for 72 h, atorvastatin (10 μM) for 48 h or pitavastatin (1 μM) for 72 h. ***P⩽0.001; **P⩽0.01. Error bars = mean ± standard error of mean (n=3). PS: phosphatidylserine; DMSO: dimethylsulfoxide.