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      Oxidized ATM-mediated glycolysis enhancement in breast cancer-associated fibroblasts contributes to tumor invasion through lactate as metabolic coupling

      research-article
      Author(s): a , 1 , a , b , c , 1 , a , d , a , a , a , a , a , e , a , *
      Publication date (Electronic):
      Journal: EBioMedicine
      Publisher: Elsevier
      Keywords: CAFs, Oxidized-ATM, Hypoxia, GLUT1, PKM2(PYKM2), ATM, ataxia-telangiectasia mutated protein kinase, DSB, double-strand break, PSCs, pancreatic stellate cells, CAFs, cancer-associated fibroblasts, NFs, normal fibroblasts, GLUT1, glucose transporter 1, PKM2 (PYKM2), pyruvate kinase M2, ROS, reactive oxygen species, HnRNP, heterogeneous nuclear ribonucleoprotein, TCA, mitochondrial tricarboxylic acid, hTERT, human telomerase reverse transcriptase gene, shRNA, short hairpin RNA, CM, conditioned medium, ECM, extracellular matrix, TEM, Transmission Electron Microscope, CCD, Charge Coupled Device, 2-DG, 2-Deoxy-Glucose, CHC, α-cyano-4-hydroxycinnamic acid, H&E, hematoxylin and eosin, IF, immunofluorescence, LC-MS/MS, liquid chromatography-tandem mass spectrometry, NAC, N-Acetylcysteine, MCT4, monocarboxylate transporter4, MCT1, monocarboxylate transporter1, OXPHOS, oxidative phosphorylation, OCR, oxygen-consumption rate, ECAR, extracellular acidification rate, FN, fibronectin, α –SMA, α-smooth muscle actin, FAP, fibroblast activation protein

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          Abstract

          Background

          Cancer-associated fibroblasts (CAFs) are the predominant residents in the breast tumor microenvironment. In our work, we found activation of DNA damage-independent ATM (oxidized ATM), enhanced glycolysis and aberrant metabolism-associated gene expressions in breast CAFs. Nevertheless, whether and how oxidized ATM regulates the glycolytic activity of CAFs keep in unveil. Recently, a reverse Warburg effect was observed in tumor tissues, in which host cells (such as CAFs, PSCs) in the tumor microenvironment have been found to “fuel” the cancer cells via metabolites transfer. However, the molecular mechanisms of the metabolites from stromal cells playing a role to the progression of cancer cells remain to be determined.

          Methods

          Oxidized ATM activation in stromal CAFs was assessed by western blotting and immunofluorescence. The increased glycolytic ability of CAFs was validated by measurements of OCR and ECAR and detections of glucose consumption and lactate production. Kinase assay and western blotting were performed to confirm the phosphorylation of GLUT1. The membrane location of phosphorylated GLUT1 was determined by biotin pull-down assay and immunofluorescence staining. The regulation of PKM2 through oxidized ATM was evaluated by western blots. In addition, the impact of lactate derived from hypoxic CAFs on cancer cell invasion was investigated both in vitro (transwell assays, western blots) and in vivo (orthotopic xenografts).

          Findings

          Hypoxia-induced oxidized ATM promotes glycolytic activity of CAFs by phosphorylating GLUT1 at S490 and increasing PKM2 expression. Moreover, lactate derived from hypoxic CAFs, acting as a metabolic coupling between CAFs and breast cancer cells, promotes breast cancer cell invasion by activating the TGFβ1/p38 MAPK/MMP2/9 signaling axis and fueling the mitochondrial activity in cancer cells.

          Interpretation

          Our work shows that oxidized ATM-mediated glycolysis enhancement in hypoxic stromal fibroblasts plays an essential role in cancer cell invasion and metastasis and may implicate oxidized ATM as a target for breast tumor treatment.

          Fund

          This research was supported by National Natural Science Foundation of China.

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          Most cited references37

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          Targeting lactate metabolism for cancer therapeutics.

          Joanne R. Doherty, John L. Cleveland (2013)
          Lactate, once considered a waste product of glycolysis, has emerged as a critical regulator of cancer development, maintenance, and metastasis. Indeed, tumor lactate levels correlate with increased metastasis, tumor recurrence, and poor outcome. Lactate mediates cancer cell intrinsic effects on metabolism and has additional non-tumor cell autonomous effects that drive tumorigenesis. Tumor cells can metabolize lactate as an energy source and shuttle lactate to neighboring cancer cells, adjacent stroma, and vascular endothelial cells, which induces metabolic reprogramming. Lactate also plays roles in promoting tumor inflammation and in functioning as a signaling molecule that stimulates tumor angiogenesis. Here we review the mechanisms of lactate production and transport and highlight emerging evidence indicating that targeting lactate metabolism is a promising approach for cancer therapeutics.
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            ATM activation by oxidative stress.

            Zhi Guo Guo, Sergei Kozlov, Martin F. Lavin … (2010)
            The ataxia-telangiectasia mutated (ATM) protein kinase is activated by DNA double-strand breaks (DSBs) through the Mre11-Rad50-Nbs1 (MRN) DNA repair complex and orchestrates signaling cascades that initiate the DNA damage response. Cells lacking ATM are also hypersensitive to insults other than DSBs, particularly oxidative stress. We show that oxidation of ATM directly induces ATM activation in the absence of DNA DSBs and the MRN complex. The oxidized form of ATM is a disulfide-cross-linked dimer, and mutation of a critical cysteine residue involved in disulfide bond formation specifically blocked activation through the oxidation pathway. Identification of this pathway explains observations of ATM activation under conditions of oxidative stress and shows that ATM is an important sensor of reactive oxygen species in human cells.
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              Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells.

              Sybille Mazurek (2011)
              Cell proliferation only proceeds when metabolism is capable of providing a budget of metabolic intermediates that is adequate to ensure both energy regeneration and the synthesis of cell building blocks in sufficient amounts. In tumor cells, the glycolytic pyruvate kinase isoenzyme M2 (PKM2, M2-PK) determines whether glucose is converted to lactate for regeneration of energy (active tetrameric form, Warburg effect) or used for the synthesis of cell building blocks (nearly inactive dimeric form). This review discusses the regulation mechanisms of pyruvate kinase M2 expression by different transcription factors as well as the regulation of pyruvate kinase M2 activity by direct interaction with certain oncoproteins, tyrosine and serine phosphorylation, binding of phosphotyrosine peptides, association with other glycolytic and non glycolytic enzymes, the promyelocytic leukemia tumor suppressor protein, as well as metabolic intermediates. An intervention in the regulation mechanisms of the expression, activity and tetramer to dimer ratio of pyruvate kinase M2 has severe consequences for metabolism as well as proliferation and tumorigenic capacity of the cells which makes this enzyme a promising target for potential therapeutic approaches. The quantification of the dimeric form of pyruvate kinase M2 (Tumor M2-PK) in plasma and stool allows early detection of tumors and therapy control. Several different mechanisms may induce a translocation of pyruvate kinase M2 into the nucleus. The role of pyruvate kinase M2 in the nucleus is complex as witnessed by evidence of its effect both as pro-proliferative as well as pro-apoptotic stimuli. Copyright © 2010 Elsevier Ltd. All rights reserved.
              Article 0 comments Cited 232 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Manran Liu
                Journal
                Journal ID (nlm-ta): EBioMedicine
                Journal ID (iso-abbrev): EBioMedicine
                Title: EBioMedicine
                Publisher: Elsevier
                ISSN (Electronic): 2352-3964
                Publication date PMC-release: 22 February 2019
                Publication date Collection: March 2019
                Publication date (Electronic): 22 February 2019
                Volume: 41
                Pages: 370-383
                Affiliations
                [a ]Key Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China
                [b ]Department of Laboratory Medicine, Liuzhou Traditional Chinese Medical Hospital, Liuzhou 545001, Guangxi, China
                [c ]Department of Laboratory Medicine, The Third Affiliated Hospital of Guangxi University of Chinese Medicine, Liuzhou 545001, Guangxi, China
                [d ]Experimental Teaching Center of Basic Medicine Science, Chongqing Medical University, Chongqing 400016, China
                [e ]Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 91006, USA
                Author notes
                [* ]Corresponding author at: Key Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, No.1, Yi-Xue-Yuan Road, Yu-zhong District, Chongqing 400016, China. manranliu@ 123456cqmu.edu.cn
                [1]

                Kexin Sun and Shifu Tang contributed equally to this work.

                Article
                Publisher ID: S2352-3964(19)30097-0
                DOI: 10.1016/j.ebiom.2019.02.025
                PMC ID: 6442874
                PubMed ID: 30799198
                SO-VID: b04e8df4-421e-4dda-92cd-7439b10ff919
                Copyright © © 2019 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 25 September 2018
                Date revision received : 31 January 2019
                Date accepted : 13 February 2019
                Categories
                Subject: Research paper

                Keywords: cafs,oxidized-atm,hypoxia,glut1,pkm2(pykm2),atm, ataxia-telangiectasia mutated protein kinase,dsb, double-strand break,pscs, pancreatic stellate cells,cafs, cancer-associated fibroblasts,nfs, normal fibroblasts,glut1, glucose transporter 1,pkm2 (pykm2), pyruvate kinase m2,ros, reactive oxygen species,hnrnp, heterogeneous nuclear ribonucleoprotein,tca, mitochondrial tricarboxylic acid,htert, human telomerase reverse transcriptase gene,shrna, short hairpin rna,cm, conditioned medium,ecm, extracellular matrix,tem, transmission electron microscope,ccd, charge coupled device,2-dg, 2-deoxy-glucose,chc, α-cyano-4-hydroxycinnamic acid,h&e, hematoxylin and eosin,if, immunofluorescence,lc-ms/ms, liquid chromatography-tandem mass spectrometry,nac, n-acetylcysteine,mct4, monocarboxylate transporter4,mct1, monocarboxylate transporter1,oxphos, oxidative phosphorylation,ocr, oxygen-consumption rate,ecar, extracellular acidification rate,fn, fibronectin,α –sma, α-smooth muscle actin,fap, fibroblast activation protein
                Data availability:
                Keywords: cafs, oxidized-atm, hypoxia, glut1, pkm2(pykm2), atm, ataxia-telangiectasia mutated protein kinase, dsb, double-strand break, pscs, pancreatic stellate cells, cafs, cancer-associated fibroblasts, nfs, normal fibroblasts, glut1, glucose transporter 1, pkm2 (pykm2), pyruvate kinase m2, ros, reactive oxygen species, hnrnp, heterogeneous nuclear ribonucleoprotein, tca, mitochondrial tricarboxylic acid, htert, human telomerase reverse transcriptase gene, shrna, short hairpin rna, cm, conditioned medium, ecm, extracellular matrix, tem, transmission electron microscope, ccd, charge coupled device, 2-dg, 2-deoxy-glucose, chc, α-cyano-4-hydroxycinnamic acid, h&e, hematoxylin and eosin, if, immunofluorescence, lc-ms/ms, liquid chromatography-tandem mass spectrometry, nac, n-acetylcysteine, mct4, monocarboxylate transporter4, mct1, monocarboxylate transporter1, oxphos, oxidative phosphorylation, ocr, oxygen-consumption rate, ecar, extracellular acidification rate, fn, fibronectin, α –sma, α-smooth muscle actin, fap, fibroblast activation protein

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