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Polyol Pathway Links Glucose Metabolism to the Aggressiveness

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Polyol Pathway Links Glucose Metabolism to the Aggressiveness Published OnlineFirst January 17, 2018; DOI: 10.1158/0008-5472.CAN-17-2834 Cancer Metabolism and Chemical Biology Research Polyol Pathway Links Glucose Metabolism to the Aggressiveness of Cancer Cells Annemarie Schwab1, Aarif Siddiqui1, Maria Eleni Vazakidou1, Francesca Napoli1, Martin Bottcher€ 2, Bianca Menchicchi3, Umar Raza4, Ozge€ Saatci4, Angela M. Krebs5, Fulvia Ferrazzi6, Ida Rapa7, Katja Dettmer-Wilde8, Maximilian J. Waldner3, Arif B. Ekici6, Suhail Ahmed Kabeer Rasheed9, Dimitrios Mougiakakos2, Peter J. Oefner8, Ozgur Sahin4, Marco Volante7, Florian R. Greten10, Thomas Brabletz5, and Paolo Ceppi1 Abstract Cancer cells alter their metabolism to support their malig- sequencing confirmed a profound alteration of EMT in PP- nant properties. In this study, we report that the glucose- deficient cells, revealing a strong repression of TGFb signature transforming polyol pathway (PP) gene aldo-keto-reductase- genes. Excess glucose was found to promote EMT through 1-member-B1 (AKR1B1) strongly correlates with epithelial-to- autocrine TGFb stimulation, while PP-deficient cells were mesenchymal transition (EMT). This association was con- refractory to glucose-induced EMT. These data show that PP firmed in samples from lung cancer patients and from an represents a molecular link between glucose metabolism, can- EMT-driven colon cancer mouse model with p53 deletion. In cer differentiation, and aggressiveness, and may serve as a novel vitro, mesenchymal-like cancer cells showed increased AKR1B1 therapeutic target. levels, and AKR1B1 knockdown was sufficient to revert EMT. An Significance: A glucose-transforming pathway in TGFb-driven equivalent level of EMT suppression was measured by targeting epithelial-to-mesenchymal transition provides novel mecha- the downstream enzyme sorbitol-dehydrogenase (SORD), fur- nistic insights into the metabolic control of cancer differenti- ther pointing at the involvement of the PP. Comparative RNA ation. Cancer Res; 78(7); 1604–18. Ó2018 AACR. Introduction types, and the corresponding CSC population in particular (6), are highly dependent on glucose metabolism and aerobic glycol- Differentiation and phenotypical heterogeneity have a funda- ysis, which they use as a major pathway for biosynthesis (7), and mental impact on the aggressiveness of tumors (1, 2). Epithelial- the molecular connection between glucose metabolism, EMT and to-mesenchymal transition (EMT) is a dedifferentiation process CSCs has recently started to emerge (6, 8, 9). Importantly, epi- that cancer cells use to acquire an invasive, chemoresistant phe- demiologic and experimental studies have connected sucrose/ notype as well as the properties of cancer stem cells (CSC; refs. 3, fructose consumption with increased cancer risk (10–12), but the 4). EMT/CSCs are therefore therapeutically very attractive, but a molecular determinants are still undefined and the impact of further understanding of the underlying biological processes is other glucose-related pathways has been poorly investigated. By required to develop novel effective therapeutics (5). Some cancer means of an unbiased transcriptomic analysis aimed at identify- ing genes highly correlated with aggressive EMT-driven tumors, 1Junior Research Group 1, Interdisciplinary Center for Clinical Research, Frie- we found the aldo-keto reductase family 1, member B1 (AKR1B1). drich-Alexander-University Erlangen-Nurnberg€ (FAU), Erlangen, Germany. This gene encodes for a specific member of the aldo-keto reductase 2Department of Internal Medicine 5, Hematology and Oncology, University superfamily catalyzing the reduction of glucose to sorbitol (13), Hospital Erlangen, Erlangen, Germany. 3Department of Medicine 1, University the first step of the polyol pathway (PP). Using different models, Hospital Erlangen, Erlangen, Germany. 4Department of Molecular Biology and 5 we provide evidence that the PP can functionally regulate EMT, Genetics, Bilkent University, Ankara, Turkey. Experimental Medicine I, FAU representing a novel link between glucose metabolism and tumor Erlangen-Nurnberg,€ Erlangen, Germany. 6Institute of Human Genetics, Frie- drich-Alexander-Universitat€ Erlangen-Nurnberg,€ Erlangen, Germany. 7Patholo- aggressiveness. gy Unit, San Luigi Hospital, University of Turin, Turin, Italy. 8Institute of Func- tional Genomics University of Regensburg, Regensburg, Germany. 9Duke-NUS Medical School, Singapore. 10Georg-Speyer-Haus, Institute for Tumor Biology Materials and Methods and Experimental Therapy, Frankfurt am Main, Germany. Cell lines and treatments Note: Supplementary data for this article are available at Cancer Research All cell lines were cultured in media supplemented with 5% Online (http://cancerres.aacrjournals.org/). FBS, 1% penicillin/streptomycin and 1% L-glutamine (Sigma) at Corresponding Author: Paolo Ceppi, Interdisciplinary Center for Clinical 37 C and 5% CO2 in a humidified incubator. Cells were from Research, Friedrich-Alexander-University Erlangen-Nurnberg€ (FAU), Niko- the National Cancer Institute (those part of the NCI-60 panel, laus-Fiebiger-Zentrum, Gluckstrasse€ 6, Erlangen 91054, Germany. Phone: except MDA-MB-231 and HCT116) or from ATCC, were STR- 4909-13185-39300; Fax: 49091-31853-6386; E-mail: profiling authenticated and used between passages 3 and 15, were [email protected] examined for the presence of mycoplasma and maintained in doi: 10.1158/0008-5472.CAN-17-2834 Plasmocin to prevent contamination (detection kit and reagents Ó2018 American Association for Cancer Research. from Invivogen). Breast (T47D, MCF-7, MDA-MB-231, BT549, 1604 Cancer Res; 78(7) April 1, 2018 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst January 17, 2018; DOI: 10.1158/0008-5472.CAN-17-2834 Polyol Pathway in Aggressive Cancers Hs578T), ovarian (Ovcar -4,-5,-8, HeyA8), lung (A549, Calu-1, Biotech). Bands were detected using the Pierce ECL Western H1299), colorectal (KM12 and Colo205), as well as renal CAKI-1 Blotting Substrate (Thermo Fisher Scientific), X-ray CL-XPosure and glioblastoma U251 cancer cell lines were cultured in RPMI films (Thermo Fisher Scientific) and the automatic film processor (Sigma). Other colorectal cancer cell lines (HCT116, HT29) were CP1000 (AGFA). cultured in McCoy 5A (Gibco). 293T and KPC(Z) cell lines were fl cultured in DMEM (Sigma). Immuno uorescence Immunofluorescence staining of cells grown on cover slips was In vitro treatments performed as described previously (14). Signals were visualized For EMT induction, cells were treated with 10 ng/mL using Leica DM5500B fluorescence microscope and Leica Appli- TGFb (R&D Systems) for 2–3 days or with 50 or 100 mmol/L cation Suite-X software. glucose (Sigma) for 3–6 days. Inhibition of TGFb signaling was performed with a neutralizing TGFb 1, 2, 3 antibody (R&D Colony formation assay Systems, 1D11, 1 mg/mL) in the presence of either 11 mmol/L To assess clonogenic ability, a colony formation assay was (concentration of standard media formulation) or 100 mmol/L performed using cells plated at a low density (1,000 cells/well), glucose for 6 days. The corresponding IgG1 isotype antibody (R&D as described previously (14). Systems, 11711, 1 mg/mL) served as a control. To test the sensitivity toward cisplatin, cells were treated with 350 or 500 mmol/L Extracellular flux assays cisplatin (Sigma) the day after plating, using DMSO as control. Bioenergetics of control and knockdown cell lines were deter- mined using the XFe96 Extracellular Flux Analyzer (Seahorse Stable overexpression and knockdown of plasmid DNA and Bioscience/Agilent Technologies). Cells were seeded in special- shRNA ized cell culture microplates at a density of 2,000 cells/well Overexpression experiments were performed as described pre- and cultured for 72 hours. One hour before the measurement, viously (14) using the EX-C0237-Lv105 construct (Genecopoeia) cells were incubated at 37 CinaCO2-free atmosphere. For the for AKR1B1. Stable knockdown of human AKR1B1 and SORD determination of glycolytic parameters, basal extracellular acid- expression was achieved using Sigma MISSION lentiviral trans- ification rate (ECAR; indicative of glycolysis) was first determined duction particles (TRCN0000288741 and TRCN0000288812 under glucose-free conditions. Second, the rate of glycolysis for AKR1B1-; TRCN0000028052, TRCN0000028069 and was calculated using the ECAR after glucose supplementation TRCN0000028106 for SORD- knockdown) and nontargeting (10 mmol/L). For the determination of respiratory parameters, controls. Cells were selected in media containing 3 mg/mL puro- basal oxygen consumption rate (OCR, indicator for mitochon- mycin (Sigma). drial respiration) was measured. All experiments were performed in pentaplicates. Raw values were normalized to the total protein Transient siRNA transfection content for each well. Transient transfections were performed using siPORT NeoFX transfection agent (Applied Biosystems) according to the manu- Flow cytometry facturer's instruction. A total of 8 Â 104 cells were transfected in The proportion of cancer stem cells was determined using the 12-well plates with 50 nmol/L siRNA (Ambion). Aldefluor Kit (StemCell Technologies) according to the man- ufacturer's instruction. Propidium iodide (PI; Sigma) staining Real-time live-cell assays was performed as described previously (14). Cells were ana- Cell proliferation and migration were monitored using live lyzed with FACSCalibur (BD Biosciences) and FlowJo (Treestar time-lapse images recorded with
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