Caffeine suppresses the progression of human glioblastoma via cathepsin B and MAPK signaling pathway.
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.
Graduate Institute of Life Science, National Defense Medical Center, Taipei, Taiwan.
Yu-Chen
YC
Cheng
Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan.
You-Ming
YM
Ding
Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center; Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan.
Dueng-Yuan
DY
Hueng
Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan.
Jang-Yi
JY
Chen
Graduate Institute of Life Science, National Defense Medical Center, Taipei, Taiwan; Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan. Electronic address: ychen0523@mail.ndmctsgh.edu.tw.
Ying
Y
Chen
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002110:Caffeine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002401:Cathepsin B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007274:Injections, Intraperitoneal; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control; D009363:Neoplasm Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; D000697:Central Nervous System Stimulants; D009363:Neoplasm Proteins; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D002110:Caffeine; C533912:CTSB protein, human; D002401:Cathepsin B; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2
Caffeine; Cathepsin B; Glioma; Invasion; MAPK