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Mitochondrial F1fo-ATP Synthase Translocates to Cell Surface in Hepatocytes and Has High Activity in Tumor-Like Acidic and Hypoxic Environment

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Mitochondrial F1fo-ATP Synthase Translocates to Cell Surface in Hepatocytes and Has High Activity in Tumor-Like Acidic and Hypoxic Environment Acta Biochim Biophys Sin 2010, 42: 530–537 | ª The Author 2010. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. DOI: 10.1093/abbs/gmq063. Original Article Mitochondrial F1Fo-ATP synthase translocates to cell surface in hepatocytes and has high activity in tumor-like acidic and hypoxic environment Zhan Ma 1†, Manlin Cao 2†, Yiwen Liu 1, Yiqing He 1, Yingzhi Wang 1, Cuixia Yang 1, Wenjuan Wang 1, Yan Du 1, Muqing Zhou 1, and Feng Gao 1* 1Department of Molecular Biology Laboratory, Shanghai Sixth People’s Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China Downloaded from 2Department of Rehabilitation Medicine, Shanghai Sixth People’s Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China †These authors contributed equally to this work. *Correspondence address. Tel: þ86-21-64369181; Fax: þ86-21-63701361; E-mail: [email protected] abbs.oxfordjournals.org F1Fo-ATP synthase was originally thought to exclusively Introduction locate in the inner membrane of the mitochondria. However, recent studies prove the existence of ectopic Using the electrochemical gradient across the inner mem- F1Fo-ATP synthase on the outside of the cell membrane. brane of the mitochondria that is generated during oxi- Ectopic ATP synthase was proposed as a marker for dative phosphorylation, F1Fo-ATP synthase generates energy by coupling the transmembrane delivery of protons tumor target therapy. Nevertheless, the protein transport at Shanghai Jiao Tong University on October 20, 2010 mechanism of the ectopic ATP synthase is still unclear. to the synthesis of ATP [1]. For a long time, F1Fo-ATP The specificity of the ectopic ATP synthase, with regard synthase was thought to exclusively locate in the inner to tumors, is questioned because of its widespread membrane of mitochondria. However, more and more evi- expression. In the current study, we constructed green flu- dence hints at the existence of F1Fo-ATP synthase on the orescent protein-ATP5B fusion protein and introduced it outside of the plasma membrane of tumor cells and some into HepG2 cells to study the localization of the ATP types of normal cells, such as endothelial cells, hepato- synthase. The expression of ATP5B was analyzed in six cytes, and adipocytes [2]. cell lines with different ‘malignancies’. These cells were Ectopic ATP synthase always localizes on the lipid rafts cultured in both normal and tumor-like acidic and or caveolae of the cytoplasmic membrane [3–5]. The hypoxic conditions. The results suggested that the ectopic mechanisms responsible for the protein transport have not expression of ATP synthase is a consequence of transloca- been established. Wang et al.[6] found that cholesterol tion from the mitochondria. The expression and catalytic loading increased the level of ATP synthase of the cyto- activity of ectopic ATP synthase were similar on the plasmic membrane. However, no increased overall surface of malignant cells as on the surface of less malig- expression of the protein was observed. It was reported that nant cells. Interestingly, the expression of ectopic ATP most of the proteins localized to the inner membrane of synthase was not up-regulated in tumor-like acidic and mitochondria could also be found on the cytoplasmic mem- hypoxic microenvironments. However, the catalytic brane [7]. Therefore, Wang et al. hypothesized that ectopic activity of ectopic ATP synthase was up-regulated in ATP synthase might translocate from the mitochondria. tumor-like microenvironments. Therefore, the specificity However, no direct evidence has been observed to support of ectopic ATP synthase for tumor target therapy relies this hypothesis until now. on the high level of catalytic activity that is observed in Ectopic ATP synthase not only functions as energy gen- acidic and hypoxic microenvironments in tumor tissues. erators but also as proton channels and receptors for various ligands, which are involved in numerous biological Keywords tumor marker; ATP synthase; plasma processes including the mediation of intracellular pH, membrane; translocation; tumor-like microenvironment cholesterol homeostasis, the regulation of the proliferation and differentiation of endothelial cells, and the recognition Received: March 5, 2010 Accepted: May 10, 2010 of immune responses of tumor cells [2]. Some proteomic Acta Biochim Biophys Sin (2010) | Volume 42 | Issue 8 | Page 530 Ectopic ATP synthase–translocation and the existence in tumor microenvironments analysis of membrane fractions indicate that the expression 40 mmHg. For all experiments, the cells were dissociated of ectopic ATP synthase in certain ‘malignant’ cells tends by incubation with PBS containing 2 mM EDTA (pH 7.4). to be higher than in ‘less malignant’ cells [8–11]. Since this molecule is involved in the regulation of endothelial cells, ectopic ATP synthase may serve as a marker for both Plasmids All kits for gene cloning were from Takara (Dalian, anti-tumor and anti-angiogenesis therapies. Some in vitro TM and in vivo research suggested that the proliferation of vas- China), except for Trizol (Invitrogen, Carlsbad, USA). cular endothelial cells and certain tumor cells could be The expression plasmid for the GFP-ATP5B fusion protein was prepared as follows: total mRNA was isolated from inhibited by anti-ATP synthase antibodies or inhibitors of TM ATP synthase [12,13]. For anti-tumor and anti-angiogenesis HUVECs using the Trizol reagent according to the man- therapy, specificity for tumor tissues should be considered. ufacturer’s instructions, and then was reverse-transcribed First, one should consider whether or not the expression and into single-stranded cDNA using AMV Reverse Transcriptase (Takara). The ATP5B precursor (ATP5Bp) activity of ectopic ATP synthase in ‘malignant’ cells are Downloaded from always higher than in ‘less malignant’ cells. Second, one coding sequence (with mitochondrial signal sequence) was 0 should also consider whether ATP synthase could be regu- PCR-amplified using the primers 5 -AACAAGCTTGCCA 0 0 lated by tumor-like acidic and hypoxic microenvironments. CCATGTTGGGGTTTG-3 and 5 -GCACGGCGAATTCT 0 To visualize the protein transport of the ectopic ATP CGATGAATGCTCTT-3 . The mature ATP5B (ATP5Bm) coding sequence (without mitochondrial signal sequence) synthase which located on the cell surface, the b-subunit of abbs.oxfordjournals.org 0 the ATP synthase gene (ATP5B) was cloned and was then PCR-amplified using primers 5 -TCGAAGCTTG 0 0 co-expressed with the green fluorescent protein (GFP) in CCACCATGGCGCAAACATCTC-3 and 5 -GCGGCGGG 0 human hepatocarcinoma cells (HepG2). The fusion protein AACTTAAGACGATGAATGCTC-3 . The resulting PCR was visualized by immunofluorescence and confocal fragments were subsequently digested with EcoRI and microscopy. To verify the specificity of ATP synthase to HindIII, and ligated to the corresponding sites in the tumor tissues, we measured the expression and enzymatic pEGFP-N1 vector (Clontech, Mountain View, USA). The activity of ATP5B in six different cell lines by flow cytometry reading frame was confirmed by restriction enzyme diges- at Shanghai Jiao Tong University on October 20, 2010 in both normal and tumor-like acidic and hypoxic conditions. tion and DNA sequencing. Materials and Methods Transfection and microscopy HepG2 cells were transiently transfected with Cell culture and treatments LipofectamineTM 2000 (Invitrogen). Microscopy of GFP Human umbilical vein endothelial cells (HUVECs) were fusion protein was performed using a Nikon A1 confocal obtained from the Sciencell Research Laboratories microscope (Nikon, Tokyo, Japan) at an interval of 8 h for (Carlsbad, USA). Human hepatocellular liver carcinoma a total duration of 48 h. The mitochondria were visualized cell line HepG2, hepatic cell line L-02, human highly by MitoTrackerTM Red (Invitrogen) staining. metastatic lung cancer cell line 95-D, human lung cancer cell line A549, and human embryonic kidney cell line 293 were obtained from the Cell Bank of Type Culture Immunofluorescence microscopy Collection of the Chinese Academy of Sciences (Shanghai, Transfected HepG2 were plated at 2 Â 105 cells/ml on China). The cells were cultured in RPMI 1640 medium glass coverslips and allowed to adhere overnight. The cov- supplemented with FCS, glutamine and antibiotics except erslips were then washed with PBS and fixed in 2% paraf- for HepG2 (DMEM), A549 (F12-K), and HUVECs ormaldehyde. A control slide was permeabilized in 0.5% (EGMTM-2). Except EGMTM-2 medium (LONZA, Triton X-100 for 15 min at room temperature after fixation. Walkersville, USA), all media are from Gibco (Carlsbad, Cells were washed by PBS and incubated at 48C overnight USA). The cells were incubated at 378C under normal (5% in PBS (pH 7.0) containing 1% bovine serum albumin CO2, 20% O2) or tumor-like low pH and hypoxic (17% (BSA) with murine monoclonal anti-GFP IgG (Beyotime, CO2, 0.5% O2, and N2 balanced) conditions. The gaseous Nantong, China) or 10% goat serum (Biostar, Wuhan, environment was maintained by a ProOxC system with China). After that, cells were washed three times and incu- ProCO2 controller (Biospherix, Lacona, USA). The pH and bated at 48C for 1 h with goat anti-mouse IgG conjugated partial pressure of oxygen (PO2) of the medium were moni- to biotin (Biostar). All cells were then washed three times tored by
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