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. 2019 Jan 18;26(10):1955–1969. doi: 10.1038/s41418-018-0265-6

Fig. 5.

Fig. 5

Inhibition of mitochondrial respiration suppresses Wnt/β-catenin signaling by enhancing α-KG-mediated degradation of HIF1α. a Total levels of α-KG were upregulated in TFAM knockdown HCT116 cells as measured by IC-MS. Data represent the mean ± SD (#p < 0.05). b Diagram showing that α-KG produced from the TCA cycle promotes PHD2-dependent degradation of HIF1α. c, d Stable control and TFAM knockdown DLD1 (c) and HCT116 (d) cells were infected with either control or sh-PHD2 lentivirus to generate TFAM and PHD2 double knockdown cells. The expression of target genes downstream of Wnt/β-catenin (including LGR5, TCF7, and AXIN2) or HIF1α (including LDHA and PDK1) was determined using qRT-PCR. Data represent the mean ± SD (n = 3, #p < 0.05). e HCT116 cells were treated with α-KG (1 mM) for 24 h and cell lysates were analyzed for the expression of HIF1α using Western blotting. f The presence of α-KG decreases cell proliferation. HCT116 cells were cultured in the presence or absence of α-KG for 24 h or 48 h and the number of cells was counted. Data represent the mean ± SD (n = 3, §p < 0.001 and *p < 0.01). g HCT116 cells were treated with α-KG for 48 h. The expression of Wnt/β-catenin (including LGR5, TCF7, and AXIN2) or HIF1α target genes (including LDHA and PDK1) was determined using qRT-PCR. Data represent the mean ± SD (p < 0.0001, §p < 0.001, and #p < 0.05)