Abstract
Glioblastoma has aggressive proliferative and invasive properties. We investigated the effect of caffeine on the invasion and the anti-cancer effect in human glioblastomas. Caffeine reduced the invasion in U-87MG, GBM8401 and LN229 cells. Caffeine decreased mRNA, protein expression, and activity of cathepsin B. Besides, mRNA and protein expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) was upregulated by caffeine treatment, whereas matrix metalloproteinase-2 (MMP-2) was downregulated. The expression of Ki67, p-p38, phospforylated extracellular regulated protein kinases (p-ERK), and membranous integrin β1 and β3 was decreased by caffeine. The Rho-associated protein kinase (ROCK) inhibitor, Y27632, blocked the caffeine-mediated reduction of cathepsin B, phosphorylated focal adhesion kinase (p-FAK), and p-ERK, and invasion. Moreover, caffeine decreased the tumor size, cathepsin B and Ki67 expression in animal model. Caffeine reduced the invasion of glioma cells through ROCK-cathepsin B/FAK/ERK signaling pathway and tumor growth in orthotopic xenograft animal model, supporting the anti-cancer potential in glioma therapy.
Keywords:
Caffeine; Cathepsin B; Glioma; Invasion; MAPK.
Copyright © 2016 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents, Phytogenic / administration & dosage
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Antineoplastic Agents, Phytogenic / pharmacology
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Antineoplastic Agents, Phytogenic / therapeutic use*
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Biomarkers, Tumor / metabolism
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Brain Neoplasms / drug therapy*
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Brain Neoplasms / metabolism
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Brain Neoplasms / pathology
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Caffeine / administration & dosage
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Caffeine / pharmacology
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Caffeine / therapeutic use*
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Cathepsin B / antagonists & inhibitors*
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Cathepsin B / genetics
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Cathepsin B / metabolism
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Cell Line, Tumor
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Cell Survival / drug effects
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Central Nervous System Stimulants / administration & dosage
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Central Nervous System Stimulants / pharmacology
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Central Nervous System Stimulants / therapeutic use
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Gene Expression Regulation, Neoplastic / drug effects*
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Glioblastoma / drug therapy*
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Glioblastoma / metabolism
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Glioblastoma / pathology
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Glioma / drug therapy
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Glioma / metabolism
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Glioma / pathology
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Humans
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Injections, Intraperitoneal
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MAP Kinase Signaling System / drug effects*
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Matrix Metalloproteinase 2 / chemistry
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Matrix Metalloproteinase 2 / genetics
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Matrix Metalloproteinase 2 / metabolism
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Mice, Nude
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Neoplasm Invasiveness / pathology
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Neoplasm Invasiveness / prevention & control
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Neoplasm Proteins / agonists
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Tissue Inhibitor of Metalloproteinase-1 / agonists
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Tissue Inhibitor of Metalloproteinase-1 / genetics
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Tissue Inhibitor of Metalloproteinase-1 / metabolism
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents, Phytogenic
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Biomarkers, Tumor
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Central Nervous System Stimulants
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Neoplasm Proteins
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TIMP1 protein, human
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Tissue Inhibitor of Metalloproteinase-1
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Caffeine
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CTSB protein, human
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Cathepsin B
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MMP2 protein, human
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Matrix Metalloproteinase 2