Utilization of Rad51C promoter for transcriptional targeting of cancer cells.

Abstract

Cancer therapy that specifically targets malignant cells with minimal or no toxicity to normal tissue has been a long-standing goal of cancer research. Rad51 expression is elevated in a wide range of cancers and Rad51 promoter has been used to transcriptionally target tumor cells, however, a large size of Rad51 promoter limits its application for gene therapy. To identify novel tumor-specific promoters, we examined expression levels of Rad51 paralogs, Rad51B, Rad51C, and Rad51D as well as Rad52 in a panel of normal and tumor cell lines. We found that Rad51C is significantly overexpressed in cancer cells. The expression was up-regulated by approximately 6-fold at the mRNA level and 9-fold at the protein level. Interestingly, the 2064 bp long Rad51C promoter fragment was approximately 300-fold higher in cancer cells than in normal cells. A construct containing Rad51C promoter driving diphtheria toxin A efficiently killed several types of cancer cells with very mild effect to normal cells. These results underscore the potential of targeting the homologous recombination pathway in cancer cells and provide a proof of principle that the Rad51C promoter fragment can be used to transcriptionally target cancer cells.

• Authors: Yan Cao, Yan Xu, Lei Zhang, Zhen Li, Ying Jiang, Xiao Tian, Andrei Seluanov, Vera Gorbunova, Zhiyong Mao
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 7 Pg. 1805-11 (Apr 15 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 24742710 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Diphtheria Toxin
• Peptide Fragments
• RAD51B protein, human
• RAD51C protein, human
• RAD51D protein, human
• RAD52 protein, human
• RNA, Messenger
• Rad52 DNA Repair and Recombination Protein
• diphtheria toxin fragment A
• Luciferases, Firefly

Topics

• Cell Line, Tumor
• Cell Survival
• DNA-Binding Proteins (genetics, metabolism)
• Diphtheria Toxin (genetics)
• Gene Fusion
• Humans
• Luciferases, Firefly (biosynthesis, genetics)
• Molecular Targeted Therapy
• Peptide Fragments (genetics)
• Promoter Regions, Genetic
• RNA, Messenger (metabolism)
• Rad52 DNA Repair and Recombination Protein (genetics)
• Transcription, Genetic
• Transfection
• Up-Regulation (genetics)