Caffeine suppresses the progression of human glioblastoma via cathepsin B and MAPK signaling pathway

J Nutr Biochem. 2016 Jul;33:63-72. doi: 10.1016/j.jnutbio.2016.03.004. Epub 2016 Mar 29.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / administration & dosage
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Antineoplastic Agents, Phytogenic / therapeutic use*
  • Biomarkers, Tumor / metabolism
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Caffeine / administration & dosage
  • Caffeine / pharmacology
  • Caffeine / therapeutic use*
  • Cathepsin B / antagonists & inhibitors*
  • Cathepsin B / genetics
  • Cathepsin B / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Central Nervous System Stimulants / administration & dosage
  • Central Nervous System Stimulants / pharmacology
  • Central Nervous System Stimulants / therapeutic use
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Glioma / drug therapy
  • Glioma / metabolism
  • Glioma / pathology
  • Humans
  • Injections, Intraperitoneal
  • MAP Kinase Signaling System / drug effects*
  • Matrix Metalloproteinase 2 / chemistry
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 2 / metabolism
  • Mice, Nude
  • Neoplasm Invasiveness / pathology
  • Neoplasm Invasiveness / prevention & control
  • Neoplasm Proteins / agonists
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Tissue Inhibitor of Metalloproteinase-1 / agonists
  • Tissue Inhibitor of Metalloproteinase-1 / genetics
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents, Phytogenic
  • Biomarkers, Tumor
  • Central Nervous System Stimulants
  • Neoplasm Proteins
  • TIMP1 protein, human
  • Tissue Inhibitor of Metalloproteinase-1
  • Caffeine
  • CTSB protein, human
  • Cathepsin B
  • MMP2 protein, human
  • Matrix Metalloproteinase 2