Rational drug design: a GAGE derived peptide kills tumor cells.
The current therapy of cancer fails to completely and exclusively target tumor cells. An ideal target for cancer therapy should be expressed exclusively in tumor cells and contribute to tumorigenesis. Targeting such a candidate gene would cause cell death only in tumor cells. A cancer testis antigen, GAGE, is considered such a target as it is expressed in numerous tumors but silent in normal tissues. Contribution of GAGE to tumorigenesis is evident from the fact that overexpression of GAGE results in rescuing the cells from cell death induced by interferon-gamma, Fas, Taxol and ionizing radiation. GAGE binds to Interferon Response Factor-1 (IRF1) and decreases its abundance, thus impacting cell death pathways mediated by interferon-gamma. To dissect the region responsible for GAGE activities, five peptides encompassing the whole sequence of GAGE protein were designed. A string of arginine residues enabled the peptides to enter the cells. Surprisingly, peptide#1 consisting of N-terminal end of GAGE protein was able to induce cell death in HeLa cells. Interestingly, GAGE null HEK293 cells and primary fibroblasts were less sensitive to the cell death induced by this peptide. Furthermore, GAGE expression, endogenous or ectopic, resulted in increased sensitization to cell death induced by this peptide suggesting its dominant active properties. The tumors that express GAGE as a diagnostic marker should be sensitive to this peptide while sparing GAGE null normal tissues suggesting potential in cancer therapeutics.
Kular
Rupinder K
RK
Davee Department of Neurology, Northwestern University, Chicago, IL, USA. r-kular@northwestern.edu
Yehiely
Fruma
F
Deiss
Louis P
LP
D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology
D057846:Cell-Penetrating Peptides; D009363:Neoplasm Proteins