Enhanced suicide gene therapy by chimeric tumor-specific promoter based on HSF1 transcriptional regulation

Jinhui Wang, Mingzhong Yao, Zilai Zhang, Jinfa Gu, Yanhong Zhang, Binhua Li, Lanying Sun, Xinyuan Liu

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Two tandem cassettes, one containing the telomerase reverse transcriptase gene (hTERT) promoter upstream of a constitutively activated form of heat shock transcription factor 1 (cHSF1) and followed by the other containing the heat shock protein 70B (hsp70B) promoter (HSE) upstream of the cytosine deaminase (CD) gene, could greatly enhance the efficiency of CD gene therapy while retaining tumor specificity in vitro and in vivo. This hTERT-cHSF1/HSE promoter could restrict gene expression in tumor cells and was about 1.5-3-fold more potent than the cytomegalovirus (CMV) promoter. hTERT-cHSF1/HSE-CD transfection led to tumor cells more sensitive to 5-fluorocytosine compared with hTERT-CD and its toxicity was comparable to that of CMV-CD. Besides enhancement of promoter activity, cHSF1 overexpression itself could enhance the bystander effect of CD gene therapy that could be reversed by anti-Fas antibody. This system also led to activation of stress-related genes such as hsp70 in tumor cells, which in the presence of cell killing by the cytotoxic gene is a highly immunostimulatory event. Furthermore, a more potent anti-tumor effect of hTERT-cHSF1/HSE-CD was observed in nude mice inoculated with Bcap37 cells. No obvious activity of the hTERT-cHSF1/HSE promoter was observed in normal tissues after intravenous administration. These results indicate that the hTERT-cHSF1/HSE promoter is highly tumor-specific and strong with potential application in targeted gene therapy, and therefore may be useful for construction of vectors for systemic therapy.

Original languageEnglish (US)
Pages (from-to)315-320
Number of pages6
JournalFEBS Letters
Volume546
Issue number2-3
DOIs
StatePublished - Jul 10 2003
Externally publishedYes

Keywords

  • Cytosine deaminase
  • Fas
  • Heat shock factor
  • Heat shock protein 70
  • Telomerase reverse transcriptase
  • Tumor-specific promoter

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

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