Dataset Information

Novel mitochondrion-targeting copper(II) complex induces HK2 malfunction and inhibits glycolysis via Drp1-mediating mitophagy in HCC.

ABSTRACT: [Cu(ttpy-tpp)Br₂ ]Br (abbreviated as CTB) is a novel mitochondrion-targeting copper(II) complex synthesized by our research group, which contains tri-phenyl-phosphonium (TPP) groups as its lipophilic property. In this study, we explored how CTB affects mitochondrial functions and exerts its anti-tumour activity. Multiple functional and molecular analyses including Seahorse XF Bioanalyzer Platform, Western blot, immunofluorescence analysis, co-immunoprecipitation and transmission electron microscopy were used to elucidate the underlying mechanisms. Human hepatoma cells were subcutaneously injected into right armpit of male nude mice for evaluating the effects of CTB in vivo. We discovered that CTB inhibited aerobic glycolysis and cell acidification by impairing the activity of HK2 in hepatoma cells, accompanied by dissociation of HK2 from mitochondria. The modification of HK2 not only led to the complete dissipation of mitochondrial membrane potential (MMP) but also promoted the opening of mitochondrial permeability transition pore (mPTP), contributing to the activation of mitophagy. In addition, CTB co-ordinately promoted dynamin-related protein 1 (Drp1) recruitment in mitochondria to induce mitochondrial fission. Our findings established a previously unrecognized role for copper complex in aerobic glycolysis of tumour cells, revealing the interaction between mitochondrial HK2-mediated mitophagy and Drp1-regulated mitochondrial fission.

SUBMITTER: Li M

PROVIDER: S-EPMC7077532 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Novel mitochondrion-targeting copper(II) complex induces HK2 malfunction and inhibits glycolysis via Drp1-mediating mitophagy in HCC.

Li Mengmeng M Shao Jiangjuan J Guo Zijian Z Jin Chun C Wang Ling L Wang Feixia F Jia Yan Y Zhu Zhenzhu Z Zhang Ziji Z Zhang Feng F Zheng Shizhong S Wang Xiaoyong X

Journal of cellular and molecular medicine 20200128 5

[Cu(ttpy-tpp)Br<sub>2</sub> ]Br (abbreviated as CTB) is a novel mitochondrion-targeting copper(II) complex synthesized by our research group, which contains tri-phenyl-phosphonium (TPP) groups as its lipophilic property. In this study, we explored how CTB affects mitochondrial functions and exerts its anti-tumour activity. Multiple functional and molecular analyses including Seahorse XF Bioanalyzer Platform, Western blot, immunofluorescence analysis, co-immunoprecipitation and transmission elect ...[more]

PMID: 31994339

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Project description:Purpose:Previous studies have reported that FOXO6 is highly expressed in hepatocellular carcinoma (HCC) tissues and is associated with the prognosis of HCC patients. However, little research has been carried out to explore the role of FOXO6 in glycolysis of HCC cells and paclitaxel resistance. Today, along with the increasing incidence and mortality of HCC, chemotherapy resistance of HCC also poses a serious challenge. Therefore, this study was set out to investigate the effect of FOXO6 on glycolysis and cytotoxicity of paclitaxel in HCC cells and its potential mechanism. Patients and Methods:The levels of FOXO6 mRNA and protein were detected by qRT-PCR and Western blot, respectively. In addition, paclitaxel-resistant cell lines of HCC cells were established, whose activity was assessed by CCK-8 assay, among which the invasion ability was assessed by Transwell and the apoptosis rate by flow cytometry. What is more, glycolysis levels were evaluated by measuring glucose consumption and lactic acid production, and the protein levels of p-PI3K and p-protein kinase B (Akt) were determined by Western blot. Results:Compared with normal human hepatocytes, FOXO6 was highly expressed in HCC cells, which was of high real value for HCC. FOXO6 knockdown inhibited the proliferation and invasion and induced apoptosis of HCC cells. In addition, FOXO6 knockdown suppressed glycolysis, reversed resistance to chemotherapy in Hep3B/PTX cells and inactivated PI3K and Akt proteins, thus inhibiting the PI3K/Akt signaling pathway. Furthermore, it was found that when activated by 740Y-P, PI3K/Akt signaling pathway could resist the effects of FOXO6 knockdown on the cytotoxicity and glycolysis of paclitaxel in HCC cells. Vice versa, inhibition of PI3K/Akt pathway by LY294002 could resist the effect of FOXO6 overexpression on chemotherapy, cytotoxicity and glycolysis of HCC cells. Conclusion:FOXO6 knockdown can inhibit glycolysis of HCC cells and reduce their resistance to chemotherapy by inhibiting the PI3K/Akt signaling pathway, which may be a new target for the treatment of HCC.

Project description:Background: Diabetic retinopathy (DR) is one of the most important microvascular diseases of diabetes. Our previous research demonstrated that bile acid G-protein-coupled membrane receptor (TGR5), a novel cell membrane receptor of bile acid, ameliorates the vascular endothelial cell dysfunction in DR. However, the precise mechanism leading to this alteration remains unknown. Thus, the mechanism of TGR5 in the progress of DR should be urgently explored. Methods: In this study, we established high glucose (HG)-induced human retinal vascular endothelial cells (RMECs) and streptozotocin-induced DR rat in vitro and in vivo. The expression of TGR5 was interfered through the specific agonist or siRNA to study the effect of TGR5 on the function of endothelial cell in vitro. Western blot, immunofluorescence and fluorescent probes were used to explore how TGR5 regulated mitochondrial homeostasis and related molecular mechanism. The adeno-associated virus serotype 8-shTGR5 (AAV8-shTGR5) was performed to evaluate retinal dysfunction in vivo and further confirm the role of TGR5 in DR by HE staining, TUNEL staining, PAS staining and Evans Blue dye. Results: We found that TGR5 activation alleviated HG-induced endothelial cell apoptosis by improving mitochondrial homeostasis. Additionally, TGR5 signaling reduced mitochondrial fission by suppressing the Ca2+-PKCδ/Drp1 signaling and enhanced mitophagy through the upregulation of the PINK1/Parkin signaling pathway. Furthermore, our result indicated that Drp1 inhibited mitophagy by facilitating the hexokinase (HK) 2 separation from the mitochondria and HK2-PINK1/Parkin signaling. In vivo, intraretinal microvascular abnormalities, including retinal vascular leakage, acellular capillaries and apoptosis, were poor in AAV8-shTGR5-treated group under DR, but this effect was reversed by pretreatment with the mitochondrial fission inhibitor Mdivi-1 or autophagy agonist Rapamycin. Conclusion: Overall, our findings indicated that TGR5 inhibited mitochondrial fission and enhanced mitophagy in RMECs by regulating the PKCδ/Drp1-HK2 signaling pathway. These results revealed the molecular mechanisms underlying the protective effects of TGR5 and suggested that activation of TGR5 might be a potential therapeutic strategy for DR.

Dataset Information

Novel mitochondrion-targeting copper(II) complex induces HK2 malfunction and inhibits glycolysis via Drp1-mediating mitophagy in HCC.

Publications

Novel mitochondrion-targeting copper(II) complex induces HK2 malfunction and inhibits glycolysis via Drp1-mediating mitophagy in HCC.

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