Supplementary Figure 11: Pharmacological inhibition of PDHA1 arrests mouse and human prostate tumors. | Nature Genetics

Supplementary Figure 11: Pharmacological inhibition of PDHA1 arrests mouse and human prostate tumors.

From: Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer

Supplementary Figure 11

(a) Integrating enrichment analysis and pathway topology analysis of metabolic pathways in prostate tumours from Ptenpc-/- mice at age of 8 weeks treated with or without 3-FP for one month (n = 3, independent prostate samples). (b-e) Quantification of confocal microscopy for lipid droplets (Lipidtox; red) by lipid droplet counts per cell (b), average lipid droplets fluorescence (a.u) (c), lipid droplet counts per mm2 (d), average lipid droplets area in µm2 (e) in wild type and Ptenpc-/- prostate tissues from 8 weeks old male mice treated with 3-FP or vehicle for one month (n = 3, independent prostate samples, 5 fields). (f,g) Relative cell number quantification by crystal violet staining (f) and PDC activity measurements (g) in indicated prostate cancer cell lines treated with 3-fluoropyruvic acid (3-FP) at the indicated concentration for 6 days (n = 3, independent cell cultures). (h-j) Evaluation of tumour formation and quantification of the percentage of Ki-67 positive cells in xenotransplantation experiment in LNCaP (h), 22Rv1 (i) and PC3 (j) cells treated with 3-FP or vehicle for two months (n = 6, independent tumour samples, 5 fields and scale bar represents 50 µm). (k) Schematic representation of the role of mitochondrial and nuclear PDH complex functions in regulating glucose influx of TCA cycle and controlling the diversion of TCA cycle intermediates (or glutamine derived anaplerosis pathway) into lipogenesis. (l) Metabolic landscape describing the functional relevance of PDC complex in regulating non-canonical tumour metabolism. Contrast to classic ‘Warburg effect' where cancers rely predominantly on glycolysis and catabolic TCA cycle gets restrained, tumours could achieve another ‘anabolism oriented' reprogramming/axis by upregulating PDC and promoting PDC nuclear translocation. Nuclear PDC controls the transitory process in TCA cycle by allowing the short-lived entry and exit of carbon pool in mitochondria to fuel citrate synthesis and lipogenesis. Taking advantage of this diversion caused by nuclear PDC, the tumour cells reduce carbon consumption in TCA cycle thereby benefiting proliferation. PDC inactivation arrests nuclear PDC active cancers by abrogating both glucose influx and potential anaplerosis pathways from reductive carboxylation and glutaminolysis. The blue represents the pathways controlled by PDC. Error bars indicate s.e.m. **P < 0.01; ***P < 0.001. n.s, not significant.

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