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Reversal of the Warburg effect with DCA in PDGF‑treated human PASMC is potentiated by pyruvate dehydrogenase kinase‑1 inhibition mediated through blocking Akt/GSK‑3β signalling

  • Authors:
    • Bingbing Li
    • Yuling Zhu
    • Qing Sun
    • Chunfang Yu
    • Lian Chen
    • Yali Tian
    • Jie Yan

  • View Affiliations

  • Published online on: June 27, 2018     https://doi.org/10.3892/ijmm.2018.3745
  • Pages: 1391-1400

  • Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

There is accumulating evidence indicating that the growth inhibitory effect of dichloroacetate (DCA) on pulmonary arterial smooth muscle cells (PASMCs) may be associated with the reversal of the Warburg effect and initiation of the mitochondria‑dependent apoptotic pathway. Previous studies indicated that platelet‑derived growth factor (PDGF) promoted the Warburg effect and resulted in apoptotic resistance of PASMCs, which was attributed to activation of the phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (Akt) signalling pathway. However, the mechanism underlying the pro‑apoptotic effect of DCA on PDGF‑treated PASMCs has not been thoroughly elucidated, and the effect of the Akt/glycogen synthase kinase‑3β (GSK‑3β) pathway inhibition concomitant with the effect of DCA on PASMC proliferation remains unclear. The growth of human PASMCs and the lactate concentration in extracellular medium of PASMCs were detected by Cell Counting Kit‑8 assays and a Lactate Colorimetric Assay kit, respectively. Cell apoptosis was evaluated by fluorescence activated cell sorting. The mitochondrial membrane potential (ΔΨm) was assessed with 5,5',6,6'‑tetrachloro‑1,1',3,3'‑tetraethylbenzimidazol‑carbocyanine iodide assays. The expression levels of phosphorylated Akt and GSK‑3β, pyruvate dehydrogenase, cleaved caspase‑3, pyruvate dehydrogenase kinase‑1 (PDK‑1), hypoxia inducible factor‑1α (HIF‑1α) and hexokinase‑2 (HK‑2) were measured with western blot analysis. Confocal analyses were employed to determine HK‑2 co‑localisation with the mitochondria. The results indicated that DCA inhibited human PASMC proliferation in a dose‑dependent manner. DCA at 10 mM promoted apoptosis and the upregulation of activated caspase‑3 in PASMCs pre‑treated with 20 ng/ml PDGF‑homeodimer BB (BB). Treatment with 5 µM LY294002 produced minimal anti‑proliferative effects on human PASMCs and barely induced cellular apoptosis and caspase‑3 activation. However, co‑administration of 10 mM DCA with LY294002 significantly decreased the cell proliferation index and induced cell apoptosis and caspase‑3 activation. The combined administration of LY294002 with DCA significantly decreased lactate concentration, promoted the depolarisation of the ΔΨm and repressed HIF‑1α upregulation and HK‑2 activation in PASMCs treated with PDGF, which was attributed to the potentiation of DCA‑induced PDK‑1 inhibition by LY294002 via blockade of the Akt/GSK‑3β/HIF‑1α signalling pathway. In conclusion, inhibition of the Akt/GSK‑3β pathway improved the pro‑apoptotic effect of DCA on human PASMCs, which may be attributed to a reversal of the Warburg effect by blocking the mutual interaction between HIF‑1α and PDK‑1, consequently downregulating HK‑2. Therefore, combinatory treatment with DCA and PI3K inhibitors may represent a novel therapeutic strategy for the reversal of apoptosis resistance exhibited by PASMCs as a result of mitochondrial bioenergetic abnormalities, as well as the treatment of pulmonary vascular remodelling in pulmonary arterial hypertension.
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September-2018
Volume 42 Issue 3

Print ISSN: 1107-3756
Online ISSN:1791-244X

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  • CiteScore: 10.7
  • CiteScore Rank: Q1: #35/328 Biochemistry, Genetics and Molecular Biology
  • Source Normalized Impact per Paper (SNIP): 0.994
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Spandidos Publications style
Li B, Zhu Y, Sun Q, Yu C, Chen L, Tian Y and Yan J: Reversal of the Warburg effect with DCA in PDGF‑treated human PASMC is potentiated by pyruvate dehydrogenase kinase‑1 inhibition mediated through blocking Akt/GSK‑3β signalling. Int J Mol Med 42: 1391-1400, 2018
APA
Li, B., Zhu, Y., Sun, Q., Yu, C., Chen, L., Tian, Y., & Yan, J. (2018). Reversal of the Warburg effect with DCA in PDGF‑treated human PASMC is potentiated by pyruvate dehydrogenase kinase‑1 inhibition mediated through blocking Akt/GSK‑3β signalling. International Journal of Molecular Medicine, 42, 1391-1400. https://doi.org/10.3892/ijmm.2018.3745
MLA
Li, B., Zhu, Y., Sun, Q., Yu, C., Chen, L., Tian, Y., Yan, J."Reversal of the Warburg effect with DCA in PDGF‑treated human PASMC is potentiated by pyruvate dehydrogenase kinase‑1 inhibition mediated through blocking Akt/GSK‑3β signalling". International Journal of Molecular Medicine 42.3 (2018): 1391-1400.
Chicago
Li, B., Zhu, Y., Sun, Q., Yu, C., Chen, L., Tian, Y., Yan, J."Reversal of the Warburg effect with DCA in PDGF‑treated human PASMC is potentiated by pyruvate dehydrogenase kinase‑1 inhibition mediated through blocking Akt/GSK‑3β signalling". International Journal of Molecular Medicine 42, no. 3 (2018): 1391-1400. https://doi.org/10.3892/ijmm.2018.3745