Use of the Rad51 promoter for targeted anti-cancer therapy.
Rad51 protein, involved in homologous recombination, is overexpressed in a variety of tumors, and its expression is correlated with a poor prognosis. Here we propose to exploit the overexpression of Rad51 in cancer cells to design a Rad51 promoter-based anticancer therapy. On average, Rad51 mRNA and protein levels are increased in cancer cells four- and sixfold, respectively. Serendipitously, we discovered that when the Rad51 ORF is replaced with another ORF, the difference in promoter activity between normal and cancer cells increases to an average of 840-fold with a maximum difference of 12,500-fold. This dramatic difference in activity has high therapeutic potential. We demonstrate that the fusion of Rad51 promoter to diphtheria toxin A (DTA) gene kills a variety of cancer cell types, including breast cancer, fibrosarcoma, and cervical cancer cells, with minimal effect on normal breast epithelial cells and normal fibroblasts. Our results suggest that therapies based on the Rad51 promoter will be highly tumor specific and open new avenues for targeting a broad range of cancers.
Hine
Christopher M
CM
Department of Biology, University of Rochester, Rochester, NY 14627, USA.
Seluanov
Andrei
A
Gorbunova
Vera
V
D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D004167:Diphtheria Toxin / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D015316:Genetic Therapy; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism* / Q000628:therapy*; D016366:Open Reading Frames / Q000235:genetics; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism*
D004167:Diphtheria Toxin; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C029795:diphtheria toxin fragment A; C495153:RAD51 protein, human; D051135:Rad51 Recombinase