Interferons upregulate thymidine phosphorylase expression via JAK-STAT-dependent transcriptional activation and mRNA stabilization in human glioblastoma cells.
Overexpression of the angiogenic enzyme thymidine phosphorylase (TP) in tumor cells and/or infiltrating macrophages correlates with increased microvessel density and poor prognosis in various tumor types including glioma. The present study examined how the TP gene expression is regulated by different types of interferons (IFNs) in human T98G and A172 glioblastoma cells. Both type I (alpha, beta) and type II (gamma) IFNs upregulated TP mRNA and protein expression while inhibiting cell proliferation. IFN-induced TP mRNA accumulation was not inhibited by the protein synthesis inhibitor cycloheximide, but was strongly blocked by the transcription inhibitor actinomycin D, as well as by transcription factor decoy oligodeoxynucleotides containing the putative IFN response element or the gamma-activated sequence in the TP promoter. The Janus kinase (JAK) inhibitor AG-490 blocked both IFN-induced STAT1 (signal transducers and activators of transcription 1) phosphorylation and TP expression. All IFNs increased the stability of TP mRNA as well. In addition, IFN-evoked TP enzyme activity enhanced the cytotoxicity of 5-fluorouracil (5-FU). These findings indicate that TP expression may be upregulated by IFNs via the JAK-STAT signaling pathway and both transcriptional and posttranscriptional mechanisms. Combined treatment with IFN and 5-fluorouracil may be a useful therapeutic strategy for malignant gliomas.
Yao
Yongxue
Y
Department of Neurosurgery Department of Microbiology and Immunology, Indiana University School of Medicine and Walther Oncology Center, Indianapolis, IN 46202, USA. yo-nyao@iupui.edu
Kubota
Toshihiko
T
Sato
Kazufumi
K
Takeuchi
Hiroaki
H
Kitai
Ryuhei
R
Matsukawa
Shigeru
S
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000201:enzymology / Q000378:metabolism*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology; D005909:Glioblastoma / Q000201:enzymology / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D007202:Indicators and Reagents; D007372:Interferons / Q000494:pharmacology*; D053613:Janus Kinase 1; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor; D013778:Tetrazolium Salts; D013844:Thiazoles; D013939:Thymidine Phosphorylase / Q000096:biosynthesis*; D015534:Trans-Activators / Q000235:genetics*; D015533:Transcriptional Activation / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D007202:Indicators and Reagents; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D013778:Tetrazolium Salts; D013844:Thiazoles; D015534:Trans-Activators; D007372:Interferons; D013939:Thymidine Phosphorylase; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1; C022616:thiazolyl blue; D005472:Fluorouracil