MiR-144 overexpression as a promising therapeutic strategy to overcome glioblastoma cell invasiveness and resistance to chemotherapy
Abstract
Abstract Glioblastoma (GB) is the most aggressive and common form of primary brain tumor, characterized by fast proliferation, high invasion, and resistance to current standard treatment. The average survival rate post-diagnosis is only of 14.6 months, despite the aggressive standard post-surgery treatment approaches of radiotherapy concomitant with chemotherapy with temozolomide. Altered cell metabolism has been identified as an emerging cancer hallmark, including in GB, thus offering a new target for cancer therapies. On the other hand, abnormal expression levels of miRNAs, key regulators of multiple molecular pathways, have been correlated with pathological manifestations of cancer, such as chemoresistance, proliferation, and resistance to apoptosis. In this work, we hypothesized that gene therapy based on modulation of a miRNA with aberrant expression in GB and predicted to target crucial metabolic enzymes might impair tumor cell metabolism. We found that the increase of miR-144 levels, shown to be downregulated in U87 and DBTRG human GB cell lines, as well as in GB tumor samples, promoted the downregulation of mRNA of enzymes involved in bioenergetic pathways, with consequent alterations in cell metabolism, impairment of migratory capacity, and sensitization of DBTRG cells to a chemotherapeutic drug, the dichloroacetate (DCA). Taken together, our findings provide evidence thatmore »
- Authors:
-
- Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal, Institute for Interdisciplinary Research of the University of Coimbra, 3030-789 Coimbra, Portugal
- Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal, Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, 3000-456 Coimbra, Portugal
- Institute for Developmental Biology and Neurobiology, Johannes Gutenberg University of Mainz, 55128 Mainz, Germany
- Neuropathology Laboratory, Neurology Service, University Hospital of Coimbra, 3004-561 Coimbra, Portugal
- Neurosurgery Service, University Hospital of Coimbra, 3004-561 Coimbra, Portugal
- Neurosurgery Service, University Hospital of Coimbra, 3004-561 Coimbra, Portugal, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal
- Publication Date:
- Sponsoring Org.:
- USDOE Office of Energy Efficiency and Renewable Energy (EERE), Transportation Office. Fuel Cell Technologies Office
- OSTI Identifier:
- 1563047
- Grant/Contract Number:
- POCI-01-0145-FEDER-016390; POCI-01-0145-FEDER-007440
- Resource Type:
- Published Article
- Journal Name:
- Human Molecular Genetics
- Additional Journal Information:
- Journal Name: Human Molecular Genetics Journal Volume: 28 Journal Issue: 16; Journal ID: ISSN 0964-6906
- Publisher:
- Oxford University Press
- Country of Publication:
- United Kingdom
- Language:
- English
Citation Formats
Cardoso, Ana M. S., Sousa, Madalena, Morais, Catarina M., Oancea-Castillo, Liliana R., Régnier-Vigouroux, Anne, Rebelo, Olinda, Tão, Hermínio, Barbosa, Marcos, Pedroso, Maria C. de Lima, and Jurado, Amália S. MiR-144 overexpression as a promising therapeutic strategy to overcome glioblastoma cell invasiveness and resistance to chemotherapy. United Kingdom: N. p., 2019.
Web. doi:10.1093/hmg/ddz099.
Cardoso, Ana M. S., Sousa, Madalena, Morais, Catarina M., Oancea-Castillo, Liliana R., Régnier-Vigouroux, Anne, Rebelo, Olinda, Tão, Hermínio, Barbosa, Marcos, Pedroso, Maria C. de Lima, & Jurado, Amália S. MiR-144 overexpression as a promising therapeutic strategy to overcome glioblastoma cell invasiveness and resistance to chemotherapy. United Kingdom. https://doi.org/10.1093/hmg/ddz099
Cardoso, Ana M. S., Sousa, Madalena, Morais, Catarina M., Oancea-Castillo, Liliana R., Régnier-Vigouroux, Anne, Rebelo, Olinda, Tão, Hermínio, Barbosa, Marcos, Pedroso, Maria C. de Lima, and Jurado, Amália S. Tue .
"MiR-144 overexpression as a promising therapeutic strategy to overcome glioblastoma cell invasiveness and resistance to chemotherapy". United Kingdom. https://doi.org/10.1093/hmg/ddz099.
@article{osti_1563047,
title = {MiR-144 overexpression as a promising therapeutic strategy to overcome glioblastoma cell invasiveness and resistance to chemotherapy},
author = {Cardoso, Ana M. S. and Sousa, Madalena and Morais, Catarina M. and Oancea-Castillo, Liliana R. and Régnier-Vigouroux, Anne and Rebelo, Olinda and Tão, Hermínio and Barbosa, Marcos and Pedroso, Maria C. de Lima and Jurado, Amália S.},
abstractNote = {Abstract Glioblastoma (GB) is the most aggressive and common form of primary brain tumor, characterized by fast proliferation, high invasion, and resistance to current standard treatment. The average survival rate post-diagnosis is only of 14.6 months, despite the aggressive standard post-surgery treatment approaches of radiotherapy concomitant with chemotherapy with temozolomide. Altered cell metabolism has been identified as an emerging cancer hallmark, including in GB, thus offering a new target for cancer therapies. On the other hand, abnormal expression levels of miRNAs, key regulators of multiple molecular pathways, have been correlated with pathological manifestations of cancer, such as chemoresistance, proliferation, and resistance to apoptosis. In this work, we hypothesized that gene therapy based on modulation of a miRNA with aberrant expression in GB and predicted to target crucial metabolic enzymes might impair tumor cell metabolism. We found that the increase of miR-144 levels, shown to be downregulated in U87 and DBTRG human GB cell lines, as well as in GB tumor samples, promoted the downregulation of mRNA of enzymes involved in bioenergetic pathways, with consequent alterations in cell metabolism, impairment of migratory capacity, and sensitization of DBTRG cells to a chemotherapeutic drug, the dichloroacetate (DCA). Taken together, our findings provide evidence that the miR-144 plus DCA combined therapy holds promise to overcome GB-acquired chemoresistance, therefore deserving to be explored toward its potential application as a complementary therapeutic approach to the current treatment options for this type of brain tumor.},
doi = {10.1093/hmg/ddz099},
journal = {Human Molecular Genetics},
number = 16,
volume = 28,
place = {United Kingdom},
year = {Tue May 14 00:00:00 EDT 2019},
month = {Tue May 14 00:00:00 EDT 2019}
}
https://doi.org/10.1093/hmg/ddz099
Web of Science
Works referenced in this record:
MicroRNAs in cerebrospinal fluid identify glioblastoma and metastatic brain cancers and reflect disease activity
journal, April 2012
- Teplyuk, N. M.; Mollenhauer, B.; Gabriely, G.
- Neuro-Oncology, Vol. 14, Issue 6
Metabolic Modulation of Glioblastoma with Dichloroacetate
journal, May 2010
- Michelakis, E. D.; Sutendra, G.; Dromparis, P.
- Science Translational Medicine, Vol. 2, Issue 31
Reverse TCA cycle flux through isocitrate dehydrogenases 1 and 2 is required for lipogenesis in hypoxic melanoma cells: Reverse TCA cycle flux in hypoxia by IDH
journal, March 2012
- Filipp, Fabian V.; Scott, David A.; Ronai, Ze’ev A.
- Pigment Cell & Melanoma Research, Vol. 25, Issue 3
Regulatory role of p53 in cancer metabolism via SCO2 and TIGAR in human breast cancer
journal, February 2012
- Won, Kyu Yeoun; Lim, Sung-Jig; Kim, Gou Young
- Human Pathology, Vol. 43, Issue 2
Epigenetic silencing of miR-126 contributes to tumor invasion and angiogenesis in colorectal cancer
journal, July 2013
- Zhang, Yu; Wang, Xinying; Xu, Binghong
- Oncology Reports, Vol. 30, Issue 4
Regulation of cancer cell metabolism
journal, January 2011
- Cairns, Rob A.; Harris, Isaac S.; Mak, Tak W.
- Nature Reviews Cancer, Vol. 11, Issue 2
Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors
journal, December 2013
- Dunbar, E. M.; Coats, B. S.; Shroads, A. L.
- Investigational New Drugs, Vol. 32, Issue 3
Regulation of glucose metabolism by p53: Emerging new roles for the tumor suppressor
journal, December 2011
- Madan, Esha; Gogna, Rajan; Bhatt, Madan
- Oncotarget, Vol. 2, Issue 12
Posttranscriptional Upregulation by MicroRNAs: Posttranscriptional Upregulation by MicroRNAs
journal, November 2011
- Vasudevan, Shobha
- Wiley Interdisciplinary Reviews: RNA, Vol. 3, Issue 3
Induction of Pyruvate Dehydrogenase Kinase-3 by Hypoxia-inducible Factor-1 Promotes Metabolic Switch and Drug Resistance
journal, August 2008
- Lu, Chun-Wun; Lin, Shih-Chieh; Chen, Ko-Fan
- Journal of Biological Chemistry, Vol. 283, Issue 42
Tp53-induced Glycolysis and Apoptosis Regulator (TIGAR) Protects Glioma Cells from Starvation-induced Cell Death by Up-regulating Respiration and Improving Cellular Redox Homeostasis
journal, August 2012
- Wanka, Christina; Steinbach, Joachim P.; Rieger, Johannes
- Journal of Biological Chemistry, Vol. 287, Issue 40
Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer
journal, September 2008
- Michelakis, E. D.; Webster, L.; Mackey, J. R.
- British Journal of Cancer, Vol. 99, Issue 7
IDH1, lipid metabolism and cancer: Shedding new light on old ideas
journal, September 2015
- Bogdanovic, Elena
- Biochimica et Biophysica Acta (BBA) - General Subjects, Vol. 1850, Issue 9
Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation
journal, May 2009
- Vander Heiden, M. G.; Cantley, L. C.; Thompson, C. B.
- Science, Vol. 324, Issue 5930
Glioblastoma multiforme: Pathogenesis and treatment
journal, August 2015
- Alifieris, Constantinos; Trafalis, Dimitrios T.
- Pharmacology & Therapeutics, Vol. 152
A non-covalent strategy combining cationic lipids and CPPs to enhance the delivery of splice correcting oligonucleotides
journal, July 2010
- Trabulo, Sara; Resina, Sarah; Simões, Sérgio
- Journal of Controlled Release, Vol. 145, Issue 2
Mechanisms of miRNA-Mediated Gene Regulation from Common Downregulation to mRNA-Specific Upregulation
journal, January 2014
- Valinezhad Orang, Ayla; Safaralizadeh, Reza; Kazemzadeh-Bavili, Mina
- International Journal of Genomics, Vol. 2014
Temozolomide: Mechanisms of Action, Repair and Resistance
journal, January 2012
- Zhang, Jihong; F. G. Stevens, Malcolm; D. Bradshaw, Tracey
- Current Molecular Pharmacology, Vol. 5, Issue 1
Epidemiologic and Molecular Prognostic Review of Glioblastoma
journal, July 2014
- Thakkar, J. P.; Dolecek, T. A.; Horbinski, C.
- Cancer Epidemiology Biomarkers & Prevention, Vol. 23, Issue 10
Genome-wide expression profiling identifies deregulated miRNAs in malignant astrocytoma
journal, August 2010
- Rao, Soumya AM; Santosh, Vani; Somasundaram, Kumaravel
- Modern Pathology, Vol. 23, Issue 10
Evaluation of Consistency in Spheroid Invasion Assays
journal, June 2016
- Cisneros Castillo, Liliana R.; Oancea, Andrei-Dumitru; Stüllein, Christian
- Scientific Reports, Vol. 6, Issue 1
Wild-type IDH2 promotes the Warburg effect and tumor growth through HIF1α in lung cancer
journal, January 2018
- Li, Jiangjiang; He, Ya; Tan, Zheqiong
- Theranostics, Vol. 8, Issue 15
The Arp2/3 complex is required for lamellipodia extension and directional fibroblast cell migration
journal, April 2012
- Suraneni, Praveen; Rubinstein, Boris; Unruh, Jay R.
- The Journal of Cell Biology, Vol. 197, Issue 2
Hallmarks of Cancer: The Next Generation
journal, March 2011
- Hanahan, Douglas; Weinberg, Robert A.
- Cell, Vol. 144, Issue 5
Control of metastatic progression by microRNA regulatory networks
journal, June 2013
- Pencheva, Nora; Tavazoie, Sohail F.
- Nature Cell Biology, Vol. 15, Issue 6
Mitochondrial metabolism and cancer
journal, December 2017
- Porporato, Paolo Ettore; Filigheddu, Nicoletta; Pedro, José Manuel Bravo-San
- Cell Research, Vol. 28, Issue 3
miR-19a and miR-19b Overexpression in Gliomas
journal, July 2013
- Jia, Zhifan; Wang, Kun; Zhang, Anling
- Pathology & Oncology Research, Vol. 19, Issue 4
The Hallmarks of Cancer
journal, January 2000
- Hanahan, Douglas; Weinberg, Robert A.
- Cell, Vol. 100, Issue 1
Switching from Repression to Activation: MicroRNAs Can Up-Regulate Translation
journal, December 2007
- Vasudevan, S.; Tong, Y.; Steitz, J. A.
- Science, Vol. 318, Issue 5858
MiRNA-21 silencing mediated by tumor-targeted nanoparticles combined with sunitinib: A new multimodal gene therapy approach for glioblastoma
journal, June 2015
- Costa, Pedro M.; Cardoso, Ana L.; Custódia, Carlos
- Journal of Controlled Release, Vol. 207
TIGAR, a p53-Inducible Regulator of Glycolysis and Apoptosis
journal, July 2006
- Bensaad, Karim; Tsuruta, Atsushi; Selak, Mary A.
- Cell, Vol. 126, Issue 1
Inhibition of the MUC1-C oncoprotein induces multiple myeloma cell death by down-regulating TIGAR expression and depleting NADPH
journal, January 2012
- Yin, Li; Kosugi, Michio; Kufe, Donald
- Blood, Vol. 119, Issue 3
Defects in mitochondrial metabolism and cancer
journal, July 2014
- Gaude, Edoardo; Frezza, Christian
- Cancer & Metabolism, Vol. 2, Issue 1
miR-182 as a Prognostic Marker for Glioma Progression and Patient Survival
journal, July 2010
- Jiang, Lili; Mao, Pu; Song, Libing
- The American Journal of Pathology, Vol. 177, Issue 1
Non-canonical functions of enzymes facilitate cross-talk between cell metabolic and regulatory pathways
journal, April 2018
- Snaebjornsson, Marteinn T.; Schulze, Almut
- Experimental & Molecular Medicine, Vol. 50, Issue 4