ROS accumulation and IGF-IR inhibition contribute to fenofibrate/PPARα -mediated inhibition of Glioma cell motility in vitro

BackgroundGlioblastomas are characterized by rapid cell growth, aggressive CNS infiltration, and are resistant to all known anticancer regimens. Recent studies indicate that fibrates and statins possess anticancer potential. Fenofibrate is a potent agonist of peroxisome proliferator activated receptor alpha (PPARα) that can switch energy metabolism from glycolysis to fatty acid β-oxidation, and has low systemic toxicity. Fenofibrate also attenuates IGF-I-mediated cellular responses, which could be relevant in the process of glioblastoma cell dispersal.MethodsThe effects of fenofibrate on Glioma cell motility, IGF-I receptor (IGF-IR) signaling, PPARα activity, reactive oxygen species (ROS) metabolism, mitochondrial potential, and ATP production were analyzed in human glioma cell lines.ResultsFenofibrate treatment attenuated IGF-I signaling responses and repressed cell motility of LN-229 and T98G Glioma cell lines. In the absence of fenofibrate, specific inhibition of the IGF-IR had only modest effects on Glioma cell motility. Further experiments revealed that PPARα-dependent accumulation of ROS is a strong contributing factor in Glioma cell lines responses to fenofibrate. The ROS scavenger, N-acetyl-cysteine (NAC), restored cell motility, improved mitochondrial potential, and increased ATP levels in fenofibrate treated Glioma cell lines.ConclusionsOur results indicate that although fenofibrate-mediated inhibition of the IGF-IR may not be sufficient in counteracting Glioma cell dispersal, PPARα-dependent metabolic switch and the resulting ROS accumulation strongly contribute to the inhibition of these devastating brain tumor cells.

• Publication year

  2010

• Venue

  Molecular Cancer

• Publication date

  2010-06-22

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1186/1476-4598-9-159PMID 20569465PMCID 2912247
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Insulin-like growth factor 1 receptor targeted therapeutics: novel compounds and novel treatment strategies for cancer medicine.

  2009cited by this paper
• Inhibition of p66ShcA Longevity Gene Rescues Podocytes from HIV-1-induced Oxidative Stress and Apoptosis*

  2009influential reference
• Transient Oxidative Stress Damages Mitochondrial Machinery Inducing Persistent β-Cell Dysfunction*

  2009cited by this paper
• Antisense therapeutics for tumor treatment: the TGF-beta2 inhibitor AP 12009 in clinical development against malignant tumors.

  2008cited by this paper
• Mitochondria, PPARs, and Cancer: Is Receptor-Independent Action of PPAR Agonists a Key?

  2008cited by this paper
• Fenofibrate for cardiovascular disease prevention in metabolic syndrome and type 2 diabetes mellitus.

  2008cited by this paper
• PPARα agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition

  2008cited by this paper
• Uncoupling protein‐2 controls proliferation by promoting fatty acid oxidation and limiting glycolysis‐derived pyruvate utilization

  2008cited by this paper
• Activation of PPARα inhibits IGF‐I‐mediated growth and survival responses in medulloblastoma cell lines

  2008influential reference
• Anticancer Properties of PPARα-Effects on Cellular Metabolism and Inflammation

  2008influential reference
• Insulin-like growth factors control cell migration in health and disease.

  2007cited by this paper
• Cholesterol-like effects of selective COX inhibitors and fibrates on cellular membranes and amyloid-β production

  2007cited by this paper
• Overexpression of thioredoxin reductase 1 inhibits migration of HEK‐293 cells

  2007cited by this paper
• Inhibition of IGF-I receptor in anchorage-independence attenuates GSK-3β constitutive phosphorylation and compromises growth and survival of medulloblastoma cell lines

  2007influential reference
• Inhibition of TGF-β2 with AP 12009 in Recurrent Malignant Gliomas: From Preclinical to Phase I/II Studies

  2007cited by this paper
• Insulin-like growth factor type I biology and targeting in malignant gliomas.

  2007influential reference
• Cholesterol-Like Effects of Selective Cyclooxygenase Inhibitors and Fibrates on Cellular Membranes and Amyloid-β Production

  2007cited by this paper
• Effect of fenofibrate on oxidative DNA damage and on gene expression related to cell proliferation and apoptosis in rats.

  2007cited by this paper
• Inhibition of TGF-beta2 with AP 12009 in recurrent malignant gliomas: from preclinical to phase I/II studies.

  2007influential reference
• PPARs and their metabolic modulation: new mechanisms for transcriptional regulation?

  2007cited by this paper
• Mitochondrial dysfunction in human pathologies.

  2007cited by this paper
• Molecular targets of glioma invasion

  2007influential reference
• Phase I/II Study of Imatinib Mesylate for Recurrent Malignant Gliomas: North American Brain Tumor Consortium Study 99-08

  2006cited by this paper
• Cell therapies for glioblastoma

  2006cited by this paper
• Glucose metabolism and cancer.

  2006cited by this paper
• Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis.

  2006cited by this paper
• Peroxisome Proliferator–Activated Receptor α Activation Decreases Metastatic Potential of Melanoma Cells In vitro via Down-Regulation of Akt

  2006cited by this paper
• In vitro and in vivo effects of the PPAR-alpha agonists fenofibrate and retinoic acid in endometrial cancer

  2006cited by this paper
• p53 Regulates Mitochondrial Respiration

  2006cited by this paper
• Molecular pathology of malignant gliomas.

  2006cited by this paper
• The ADP/ATP Ratio: A Novel Predictive Assay for Quality Assessment of Isolated Pancreatic Islets

  2006cited by this paper
• Glycolytic glioma cells with active glycogen synthase are sensitive to PTEN and inhibitors of PI3K and gluconeogenesis

  2005cited by this paper
• Flavonoid apigenin inhibits motility and invasiveness of carcinoma cells in vitro

  2005cited by this paper
• Proteomic characterization of harvested pseudopodia with differential gel electrophoresis and specific antibodies

  2005cited by this paper
• MGMT gene silencing and benefit from temozolomide in glioblastoma.

  2005cited by this paper
• The Role of Radio- and Chemotherapy in Glioblastoma

  2005cited by this paper
• Activated IGF-1R inhibits hyperglycemia-induced DNA damage and promotes DNA repair by homologous recombination.

  2005cited by this paper
• In vivo antitumor activity of NVP-AEW541-A novel, potent, and selective inhibitor of the IGF-IR kinase.

  2004cited by this paper
• Transcriptome analysis of endometrial cancer identifies peroxisome proliferator-activated receptors as potential therapeutic targets.

  2004cited by this paper
• Inhibition of melanoma metastases by fenofibrate

  2004cited by this paper
• Insulin-like growth factors and neoplasia.

  2004cited by this paper
• Insulin-like growth factors and neoplasia

  2004cited by this paper
• Protective effects of green tea polyphenols on human HepG2 cells against oxidative damage of fenofibrate.

  2003cited by this paper
• Bezafibrate induces a mitochondrial derangement in human cell lines: a PPAR-independent mechanism for a peroxisome proliferator.

  2003cited by this paper
• Peroxisome Proliferator-activated Receptor α (PPARα) Signaling in the Gene Regulatory Control of Energy Metabolism in the Normal and Diseased Heart

  2002cited by this paper
• Cytotoxic effect of peroxisome proliferator fenofibrate on human HepG2 hepatoma cell line and relevant mechanisms.

  2002cited by this paper
• Peroxisome proliferator-activated receptor alpha (PPARalpha) signaling in the gene regulatory control of energy metabolism in the normal and diseased heart.

  2002cited by this paper
• Control of oxygen free radical formation from mitochondrial complex I: roles for protein kinase A and pyruvate dehydrogenase kinase.

  2002cited by this paper
• Mechanism for Peroxisome Proliferator-activated Receptor-α Activator-induced Up-regulation of UCP2 mRNA in Rodent Hepatocytes*

  2002cited by this paper
• Activation of the IGF-IR system contributes to malignant growth of human and mouse medulloblastomas

  2001cited by this paper
• Results of a pilot study involving the use of an antisense oligodeoxynucleotide directed against the insulin-like growth factor type I receptor in malignant astrocytomas.

  2001cited by this paper
• Activators of peroxisome proliferator-activated receptor-alpha partially inhibit mouse skin tumor promotion.

  2000cited by this paper
• Insulin-like growth factor I receptor antagonism augments response to chemoradiation therapy in colon cancer cells.

  2000cited by this paper
• Activators of peroxisome proliferator–activated receptor‐α partially inhibit mouse skin tumor promotion

  2000cited by this paper
• Flow Cytometric Analysis of Mitochondrial Membrane Potential Using JC‐1

  2000cited by this paper
• Anti-apoptotic signaling of the IGF-I receptor in fibroblasts following loss of matrix adhesion

  1999cited by this paper
• Frequent Co‐Alterations of TP53, p16/CDKN2A, p14ARF, PTEN Tumor Suppressor Genes in Human Glioma Cell Lines.

  1999influential reference
• Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years.

  1998cited by this paper
• Molecular markers of IGF-I-mediated mitogenesis.

  1998cited by this paper
• Metabolic interactions between glucose and fatty acids in humans.

  1998cited by this paper
• Direct phosphorylation of IkappaB by IKKalpha and IKKbeta: discrimination between free and NF-kappaB-bound substrate.

  1998cited by this paper
• Insulin‐like growth factor‐I‐mediated survival from Anoikis: Role of cell aggregation and focal adhesion kinase

  1998cited by this paper
• Direct Phosphorylation of IκB by IKKα and IKKβ: Discrimination Between Free and NF-κB-Bound Substrate

  1998cited by this paper
• Insulin-like growth factor-I receptor overexpression mediates cellular radioresistance and local breast cancer recurrence after lumpectomy and radiation.

  1997cited by this paper
• Chemotaxis of Amoeba proteus in the developing pH gradient within a pocket-like chamber studied with the computer assisted method.

  1997cited by this paper
• The IGF-I receptor in cell growth, transformation and apoptosis.

  1997cited by this paper
• Effects of hypolipidemic drugs on the expression of genes involved in high density lipoprotein metabolism in the rat.

  1996cited by this paper
• A soluble insulin-like growth factor I receptor that induces apoptosis of tumor cells in vivo and inhibits tumorigenesis.

  1996cited by this paper
• Regression of C6 rat brain tumors by cells expressing an antisense insulin-like growth factor I receptor RNA.

  1996cited by this paper
• The insulin-like growth factor I receptor protects tumor cells from apoptosis in vivo.

  1995cited by this paper
• Fibrates increase human apolipoprotein A-II expression through activation of the peroxisome proliferator-activated receptor.

  1995cited by this paper
• Lymphocyte locomotion in three-dimensional collagen gels. Comparison of three quantitative methods for analysing cell trajectories.

  1993cited by this paper
• Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators

  1990cited by this paper
• [Origin of cancer cells].

  1956cited by this paper
• On respiratory impairment in cancer cells.

  1956cited by this paper
• On the origin of cancer cells.

  1956cited by this paper
• On respiratory impairment in cancer cells.

  1956cited by this paper

• Loss of HuD Sensitizes Neuroblastoma Cells to Palmitate-Driven Stress-Induced Premature Senescence via PPARα Downregulation and FAO Impairment.

  2026cites this paper
• Discovery of PPAR Alpha Lipid Pathway Modulators That Do Not Bind Directly to the Receptor as Potential Anti-Cancer Compounds

  2025cites this paper
• Mitochondrial-Targeted Multifunctional Platinum-Based Nano "Terminal-Sensitive Projectile" for Enhanced Cancer Chemotherapy Efficacy.

  2025cites this paper
• Cardiolipin Dysregulation in Glioblastoma—Effects on Mitochondrial Function Tumor Cell Death and Sensitivity to Mitochondria‐Targeting Drugs

  2025cites this paper
• Targeting PPARα activation sensitizes glioblastoma cells to temozolomide and reverses acquired resistance by inhibiting H3K18 lactylation

  2025cites this paper
• Bypassing Blood‐Brain Barrier and Glucose Dependency of Anti‐Glioblastoma Drug Candidates Targeting Mitochondrial Respiration

  2025cites this paper
• Endothelial activation during the diapedesis of cancer cells: between the kiss of death and therapeutic breakthrough

  2025cites this paper
• Unlocking therapeutic potential: Exploring nuclear receptors in brain cancer treatment

  2025cites this paper
• Touchable Electrochemical Hydrogel Sensor for Detection of Reactive Oxygen Species‐induced Cellular Senescence in Articular Chondrocytes

  2023cites this paper
• Lipid-lowering drugs and cancer: an updated perspective

  2023cites this paper
• Natural and synthetic compounds for glioma treatment based on ROS-mediated strategy.

  2023cites this paper
• In Situ Vaccination with Mitochondria‐Targeting Immunogenic Death Inducer Elicits CD8+ T Cell‐Dependent Antitumor Immunity to Boost Tumor Immunotherapy

  2023cites this paper
• The role of peroxisome proliferator-activated receptors in the tumor microenvironment, tumor cell metabolism, and anticancer therapy

  2023cites this paper
• Overcoming Cancer Resistance to Platinum Drugs by Inhibiting Cholesterol Metabolism.

  2023cites this paper
• Repurposing of Metabolic Drugs and Mitochondrial Modulators as an Emerging Class of Cancer Therapeutics with a Special Focus on Breast Cancer

  2022cites this paper
• Anti-glioblastoma effects of phenolic variants of benzoylphenoxyacetamide (BPA) with high potential for blood brain barrier penetration

  2022cites this paper
• Potential Therapeutic Effects of PPAR Ligands in Glioblastoma

  2022cites this paper
• ALKBH family members as novel biomarkers and prognostic factors in human breast cancer

  2022cites this paper
• Long-Term Fenofibrate Treatment Stimulates the Phenotypic Microevolution of Prostate Cancer Cells In Vitro

  2022cites this paper
• Hydrogen-Iodide Bonding between Glycine and Perovskite Greatly Improve Moisture Stability for Binary PSCs

  2022cites this paper
• Resistance to antiangiogenic treatments: A review

  2022cites this paper
• Fenofibrate mediated activation of PPARα negatively regulates trophoblast invasion.

  2022cites this paper
• Peroxisome Proliferator-Activated Receptors and the Hallmarks of Cancer

  2022cites this paper
• Anti-glioblastoma Effects of Structural Variants of Benzoylphenoxyacetamide (BPA): II. Synthesis Strategies for Phenolic Variants of BPAs With Potential for Blood Brain Barrier Penetration.

  2021cites this paper
• Paracelsus Paradox and Drug Repurposing for Cancer

  2021cites this paper
• Targeting ROS-AMPK pathway by multiaction Platinum(IV) prodrugs containing hypolipidemic drug bezafibrate.

  2021cites this paper
• Metronomic anti-angiogenesis: The ideal companion of pH-centered treatments

  2020cites this paper
• Chemically Modified Variants of Fenofibrate with Antiglioblastoma Potential

  2019cites this paper
• 2-(2-(2,4-dioxopentan-3-ylidene)hydrazineyl)benzonitrile as novel inhibitor of receptor tyrosine kinase and PI3K/AKT/mTOR signaling pathway in glioblastoma.

  2019cites this paper
• Fenofibrate induces human hepatoma Hep3B cells apoptosis and necroptosis through inhibition of thioesterase domain of fatty acid synthase

  2019cites this paper
• Fenofibrate Augments the Sensitivity of Drug-Resistant Prostate Cancer Cells to Docetaxel

  2019cites this paper
• Chemically Modified Variants of Fenofibrate with Antiglioblastoma Potential 1 , 2

  2019cites this paper
• Exploring anticancer activity of structurally modified benzylphenoxyacetamide (BPA); I: Synthesis strategies and computational analyses of substituted BPA variants with high anti-glioblastoma potential

  2019cites this paper
• Synergy Between Low Dose Metronomic Chemotherapy and the pH-Centered Approach Against Cancer

  2019cites this paper
• Hydrogen Ion Dynamics of Cancer and a New Molecular, Biochemical and Metabolic Approach to the Etiopathogenesis and Treatment of Brain Malignancies

  2019cites this paper
• Deconvolution and network analysis of IDH-mutant lower grade glioma predict recurrence and indicate therapeutic targets.

  2019cites this paper
• Fenofibrate Interferes with the Diapedesis of Lung Adenocarcinoma Cells through the Interference with Cx43/EGF-Dependent Intercellular Signaling

  2018cites this paper
• TM4SF1 regulates apoptosis, cell cycle and ROS metabolism via the PPARγ-SIRT1 feedback loop in human bladder cancer cells.

  2018cites this paper
• Hints on ATGL implications in cancer: beyond bioenergetic clues

  2018cites this paper
• Anticancer Properties of Fenofibrate: A Repurposing Use

  2018cites this paper
• Fenofibrate inhibits the growth of prostate cancer through regulating autophagy and endoplasmic reticulum stress.

  2018cites this paper
• Metabolic Shift Induced by ω -3 PUFAs and Rapamycin Lead to Cancer Cell Death

  2018cites this paper
• shRNA‐mediated PPARα knockdown in human glioma stem cells reduces in vitro proliferation and inhibits orthotopic xenograft tumour growth

  2018cites this paper
• A systems biology approach to understanding Autosomal Dominant Polycystic Kidney Disease

  2018cites this paper
• SLC7A11 over-expression in glioblastoma is associated with increased cancer stem-cell like properties

  2017cites this paper
• DHA induces apoptosis of human malignant breast cancer tissues by the TLR-4/PPAR-α pathways

  2017cites this paper
• Peroxisome proliferator-activated receptor α (PPARα) contributes to control of melanogenesis in B16 F10 melanoma cells

  2017cites this paper
• Anticancer activity of salicin and fenofibrate

  2017cites this paper
• Acute Ethanol Increases IGF‐I‐Induced Phosphorylation of ERKs by Enhancing Recruitment of p52‐Shc to the Grb2/Shc Complex

  2017cites this paper
• The transcription factor PPARα is overexpressed and is associated with a favourable prognosis in IDH‐wildtype primary glioblastoma

  2017cites this paper
• PPAR-γ Agonists As Antineoplastic Agents in Cancers with Dysregulated IGF Axis

  2017cites this paper
• SLC7A11 Overexpression in Glioblastoma Is Associated with Increased Cancer Stem Cell-Like Properties

  2017cites this paper
• Anticancer potential of aminomethylidene-diazinanes I. Synthesis of arylaminomethylidene of diazinetriones and its cytotoxic effects tested in glioblastoma cells.

  2017cites this paper
• Glioblastoma-synthesized G-CSF and GM-CSF contribute to growth and immunosuppression: Potential therapeutic benefit from dapsone, fenofibrate, and ribavirin

  2017cites this paper
• Cyclin D1 represses peroxisome proliferator-activated receptor alpha and inhibits fatty acid oxidation

  2016cites this paper
• The transcription factor PPARalpha is overexpressed and is associated with a favourable prognosis in IDH-wildtype primary glioblastoma Running title : PPARalpha expression in primary glioblastoma

  2016cites this paper
• Metformin stimulates IGFBP-2 gene expression through PPARalpha in diabetic states

  2016cites this paper
• Fenofibrate Suppresses Oral Tumorigenesis via Reprogramming Metabolic Processes: Potential Drug Repurposing for Oral Cancer

  2016influential citation
• PPARα modulates gene expression profiles of mitochondrial energy metabolism in oral tumorigenesis

  2016cites this paper
• A critical overview of long non-coding RNA in glioma etiology 2016: an update

  2016cites this paper
• Epigenetics, TET proteins, and hypoxia in epithelial-mesenchymal transition and tumorigenesis

  2016influential citation
• Fenofibrate Induces Ketone Body Production in Melanoma and Glioblastoma Cells

  2016cites this paper
• Anti-tumoral Effects of miR-3189-3p in Glioblastoma*

  2015cites this paper
• Regulation of IGFBP-2 expression during fasting

  2015cites this paper
• Fenofibrate subcellular distribution as a rationale for the intracranial delivery through biodegradable carrier.

  2015cites this paper
• Fenofibrate enhances barrier function of endothelial continuum within the metastatic niche of prostate cancer cells

  2015cites this paper
• Involvement of ROS-alpha v beta 3 integrin-FAK/Pyk2 in the inhibitory effect of melatonin on U251 glioma cell migration and invasion under hypoxia

  2015cites this paper
• Changes in mitochondrial morphology induced by calcium or rotenone in primary astrocytes occur predominantly through ros‐mediated remodeling

  2015cites this paper
• Fenofibrate activates Nrf2 through p62-dependent Keap1 degradation.

  2015cites this paper
• Fenofibrate induces G0/G1 phase arrest by modulating the PPARα/FoxO1/p27kip pathway in human glioblastoma cells

  2015cites this paper
• PPARα regulates tumor progression, foe or friend?

  2015cites this paper
• Fenofibrate in cancer: mechanisms involved in anticancer activity (version 2; referees: 1 approved, 1 approved with reservations)

  2015cites this paper
• Inhibition of intracerebral glioblastoma growth by targeting the insulin-like growth factor 1 receptor involves different context-dependent mechanisms.

  2015cites this paper
• Effects of atmospheric pressure cold plasma on human hepatocarcinoma cell and its 5-fluorouracil resistant cell line

  2015cites this paper
• Fenofibrate induces apoptosis of triple-negative breast cancer cells via activation of NF-κB pathway

  2014cites this paper
• Impact des ligands de PPARs, et leurs dérivés, sur les cellules cancéreuses coliques humaines : modifications des statuts redox et glycolytique

  2014cites this paper
• Neuroprotective properties of peroxisome proliferator-activated receptor alpha (PPARα) and its lipid ligands.

  2014cites this paper
• Characterization of fenofibrate-mediated anti-proliferative pro-apoptotic effects on high-grade gliomas and anti-invasive effects on glioma stem cells

  2014influential citation
• Molecular Mechanisms of Fenofibrate-Induced Metabolic Catastrophe and Glioblastoma Cell Death

  2014influential citation
• Differential Effects of MicroRNAs on Glioblastoma Growth and Migration

  2013cites this paper
• Novel MEK inhibitor trametinib and other retinoblastoma gene (RB)‐reactivating agents enhance efficacy of 5‐fluorouracil on human colon cancer cells

  2013cites this paper
• Fenofibrate down-regulates the expressions of androgen receptor (AR) and AR target genes and induces oxidative stress in the prostate cancer cell line LNCaP.

  2013cites this paper
• The role of aryl hydrocarbon receptor-regulated cytochrome P450 enzymes in glioma.

  2013cites this paper
• Behavioral paradigms to evaluate PPAR modulation in animal models of brain injury.

  2013cites this paper
• Targeting 3-phosphoinositide-dependent protein kinase 1 by N-acetyl-cysteine through activation of peroxisome proliferators activated receptor alpha in human lung cancer cells, the role of p53 and p65

  2013cites this paper
• Peroxisome proliferator activated receptor α ligands as anticancer drugs targeting mitochondrial metabolism.

  2013cites this paper
• Fenofibrate-induced nuclear translocation of FoxO3A triggers Bim-mediated apoptosis in glioblastoma cells in vitro

  2012cites this paper
• Fenofibrate triggers apoptosis of glioblastoma cells in vitro

  2012cites this paper
• Activation of Peroxisome Proliferator-activated Receptor α (PPARα) Suppresses Hypoxia-inducible Factor-1α (HIF-1α) Signaling in Cancer Cells*

  2012cites this paper
• Fenofibrate attenuates contact-stimulated cell motility and gap junctional coupling in DU-145 human prostate cancer cell populations.

  2011cites this paper
• Comparison of the effects of the n-3 polyunsaturated fatty acid eicosapentaenoic and fenofibrate on the inhibitory effect of arthritis on IGF1.

  2011cites this paper