1H-NMR metabolomics reveals the Glabrescione B exacerbation of glycolytic metabolism beside the cell growth inhibitory effect in glioma
Abstract Background Glioma is the most common and primary brain tumors in adults. Despite the available multimodal therapies, glioma patients appear to have a poor prognosis. The Hedgehog (Hh) signaling is involved in tumorigenesis and emerged as a promising target for brain tumors. Glabrescione B (...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-08-01
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| Series: | Cell Communication and Signaling |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12964-019-0421-8 |
| _version_ | 1818280206392098816 |
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| author | Giuseppina D’Alessandro Deborah Quaglio Lucia Monaco Clotilde Lauro Francesca Ghirga Cinzia Ingallina Michela De Martino Sergio Fucile Alessandra Porzia Maria Amalia Di Castro Federica Bellato Francesca Mastrotto Mattia Mori Paola Infante Paola Turano Stefano Salmaso Paolo Caliceti Lucia Di Marcotullio Bruno Botta Veronica Ghini Cristina Limatola |
| author_facet | Giuseppina D’Alessandro Deborah Quaglio Lucia Monaco Clotilde Lauro Francesca Ghirga Cinzia Ingallina Michela De Martino Sergio Fucile Alessandra Porzia Maria Amalia Di Castro Federica Bellato Francesca Mastrotto Mattia Mori Paola Infante Paola Turano Stefano Salmaso Paolo Caliceti Lucia Di Marcotullio Bruno Botta Veronica Ghini Cristina Limatola |
| author_sort | Giuseppina D’Alessandro |
| collection | DOAJ |
| description | Abstract Background Glioma is the most common and primary brain tumors in adults. Despite the available multimodal therapies, glioma patients appear to have a poor prognosis. The Hedgehog (Hh) signaling is involved in tumorigenesis and emerged as a promising target for brain tumors. Glabrescione B (GlaB) has been recently identified as the first direct inhibitor of Gli1, the downstream effector of the pathway. Methods We established the overexpression of Gli1 in murine glioma cells (GL261) and GlaB effect on cell viability. We used 1H-nuclear magnetic resonance (NMR) metabolomic approach to obtain informative metabolic snapshots of GL261 cells acquired at different time points during GlaB treatment. The activation of AMP activated protein Kinase (AMPK) induced by GlaB was established by western blot. After the orthotopic GL261 cells injection in the right striatum of C57BL6 mice and the intranasal (IN) GlaB/mPEG5kDa-Cholane treatment, the tumor growth was evaluated. The High Performance Liquid Chromatography (HPLC) combined with Mass Spectrometry (MS) was used to quantify GlaB in brain extracts of treated mice. Results We found that GlaB affected the growth of murine glioma cells both in vitro and in vivo animal model. Using an untargeted 1H-NMR metabolomic approach, we found that GlaB stimulated the glycolytic metabolism in glioma, increasing lactate production. The high glycolytic rate could in part support the cytotoxic effects of GlaB, since the simultaneous blockade of lactate efflux with α-cyano-4-hydroxycinnamic acid (ACCA) affected glioma cell growth. According to the metabolomic data, we found that GlaB increased the phosphorylation of AMPK, a cellular energy sensor involved in the anabolic-to-catabolic transition. Conclusions Our results indicate that GlaB inhibits glioma cell growth and exacerbates Warburg effect, increasing lactate production. In addition, the simultaneous blockade of Gli1 and lactate efflux amplifies the anti-tumor effect in vivo, providing new potential therapeutic strategy for this brain tumor. Graphical Abstract |
| first_indexed | 2024-12-12T23:45:32Z |
| format | Article |
| id | doaj.art-ff7751943fc1431e869c9fb22d5bcc4c |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-12-12T23:45:32Z |
| publishDate | 2019-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj.art-ff7751943fc1431e869c9fb22d5bcc4c2022-12-22T00:06:52ZengBMCCell Communication and Signaling1478-811X2019-08-0117111210.1186/s12964-019-0421-81H-NMR metabolomics reveals the Glabrescione B exacerbation of glycolytic metabolism beside the cell growth inhibitory effect in gliomaGiuseppina D’Alessandro0Deborah Quaglio1Lucia Monaco2Clotilde Lauro3Francesca Ghirga4Cinzia Ingallina5Michela De Martino6Sergio Fucile7Alessandra Porzia8Maria Amalia Di Castro9Federica Bellato10Francesca Mastrotto11Mattia Mori12Paola Infante13Paola Turano14Stefano Salmaso15Paolo Caliceti16Lucia Di Marcotullio17Bruno Botta18Veronica Ghini19Cristina Limatola20Department of Physiology and Pharmacology, Sapienza UniversityDepartment of Chemistry and Technology of Drugs, “Department of Excellence 2018−2022”, Sapienza University of RomeDepartment of Physiology and Pharmacology, Sapienza UniversityDepartment of Physiology and Pharmacology, Sapienza UniversityCenter For Life Nano Science@Sapienza, Istituto Italiano di TecnologiaDepartment of Chemistry and Technology of Drugs, “Department of Excellence 2018−2022”, Sapienza University of RomeDepartment of Chemistry and Technology of Drugs, “Department of Excellence 2018−2022”, Sapienza University of RomeDepartment of Physiology and Pharmacology, Sapienza UniversityDepartment of Molecular Medicine, Laboratory affiliated to Istituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of RomeDepartment of Physiology and Pharmacology, Sapienza UniversityDepartment of Pharmaceutical and Pharmacological Sciences, University of PadovaDepartment of Pharmaceutical and Pharmacological Sciences, University of PadovaDepartment of Biotechnology, Chemistry and Pharmacy, “Department of Excellence 2018−2022”, University of SienaCenter For Life Nano Science@Sapienza, Istituto Italiano di TecnologiaCERM and Department of Chemistry, University of FlorenceDepartment of Pharmaceutical and Pharmacological Sciences, University of PadovaDepartment of Pharmaceutical and Pharmacological Sciences, University of PadovaDepartment of Molecular Medicine, Laboratory affiliated to Istituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of RomeDepartment of Chemistry and Technology of Drugs, “Department of Excellence 2018−2022”, Sapienza University of RomeCIRMMPIRCCS NeuromedAbstract Background Glioma is the most common and primary brain tumors in adults. Despite the available multimodal therapies, glioma patients appear to have a poor prognosis. The Hedgehog (Hh) signaling is involved in tumorigenesis and emerged as a promising target for brain tumors. Glabrescione B (GlaB) has been recently identified as the first direct inhibitor of Gli1, the downstream effector of the pathway. Methods We established the overexpression of Gli1 in murine glioma cells (GL261) and GlaB effect on cell viability. We used 1H-nuclear magnetic resonance (NMR) metabolomic approach to obtain informative metabolic snapshots of GL261 cells acquired at different time points during GlaB treatment. The activation of AMP activated protein Kinase (AMPK) induced by GlaB was established by western blot. After the orthotopic GL261 cells injection in the right striatum of C57BL6 mice and the intranasal (IN) GlaB/mPEG5kDa-Cholane treatment, the tumor growth was evaluated. The High Performance Liquid Chromatography (HPLC) combined with Mass Spectrometry (MS) was used to quantify GlaB in brain extracts of treated mice. Results We found that GlaB affected the growth of murine glioma cells both in vitro and in vivo animal model. Using an untargeted 1H-NMR metabolomic approach, we found that GlaB stimulated the glycolytic metabolism in glioma, increasing lactate production. The high glycolytic rate could in part support the cytotoxic effects of GlaB, since the simultaneous blockade of lactate efflux with α-cyano-4-hydroxycinnamic acid (ACCA) affected glioma cell growth. According to the metabolomic data, we found that GlaB increased the phosphorylation of AMPK, a cellular energy sensor involved in the anabolic-to-catabolic transition. Conclusions Our results indicate that GlaB inhibits glioma cell growth and exacerbates Warburg effect, increasing lactate production. In addition, the simultaneous blockade of Gli1 and lactate efflux amplifies the anti-tumor effect in vivo, providing new potential therapeutic strategy for this brain tumor. Graphical Abstracthttp://link.springer.com/article/10.1186/s12964-019-0421-8GliomaHh pathwayIsoflavones1H-NMR spectroscopyMetabolomics |
| spellingShingle | Giuseppina D’Alessandro Deborah Quaglio Lucia Monaco Clotilde Lauro Francesca Ghirga Cinzia Ingallina Michela De Martino Sergio Fucile Alessandra Porzia Maria Amalia Di Castro Federica Bellato Francesca Mastrotto Mattia Mori Paola Infante Paola Turano Stefano Salmaso Paolo Caliceti Lucia Di Marcotullio Bruno Botta Veronica Ghini Cristina Limatola 1H-NMR metabolomics reveals the Glabrescione B exacerbation of glycolytic metabolism beside the cell growth inhibitory effect in glioma Cell Communication and Signaling Glioma Hh pathway Isoflavones 1H-NMR spectroscopy Metabolomics |
| title | 1H-NMR metabolomics reveals the Glabrescione B exacerbation of glycolytic metabolism beside the cell growth inhibitory effect in glioma |
| title_full | 1H-NMR metabolomics reveals the Glabrescione B exacerbation of glycolytic metabolism beside the cell growth inhibitory effect in glioma |
| title_fullStr | 1H-NMR metabolomics reveals the Glabrescione B exacerbation of glycolytic metabolism beside the cell growth inhibitory effect in glioma |
| title_full_unstemmed | 1H-NMR metabolomics reveals the Glabrescione B exacerbation of glycolytic metabolism beside the cell growth inhibitory effect in glioma |
| title_short | 1H-NMR metabolomics reveals the Glabrescione B exacerbation of glycolytic metabolism beside the cell growth inhibitory effect in glioma |
| title_sort | 1h nmr metabolomics reveals the glabrescione b exacerbation of glycolytic metabolism beside the cell growth inhibitory effect in glioma |
| topic | Glioma Hh pathway Isoflavones 1H-NMR spectroscopy Metabolomics |
| url | http://link.springer.com/article/10.1186/s12964-019-0421-8 |
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