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Published on: January 7, 2019
Rational drug design: a GAGE derived peptide kills tumor cells
Rupinder K Kular1, Fruma Yehiely, Louis P Deiss
1Davee Department of Neurology, Northwestern University, Chicago, IL, USA. r-kular@northwestern.edu
Abstract:
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.
Insights
A novel peptide derived from the GAGE protein shows promise for cancer therapy. This GAGE-targeting peptide selectively induces cancer cell death, sparing normal tissues, and offers a potential new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Current cancer therapies lack specificity, often harming healthy cells.
- GAGE, a cancer-testis antigen, is exclusively expressed in tumors and promotes tumorigenesis.
- GAGE overexpression confers resistance to various cell death-inducing agents.
Purpose of the Study:
- To identify a specific region of the GAGE protein responsible for its tumor-promoting activities.
- To develop a targeted therapeutic peptide based on GAGE for cancer treatment.
- To evaluate the efficacy and specificity of GAGE-derived peptides in inducing cancer cell death.
Main Methods:
- Designed five peptides covering the entire GAGE protein sequence, incorporating arginine for cell penetration.
- Assessed the ability of these peptides to induce cell death in various cell lines, including HeLa, GAGE null HEK293, and primary fibroblasts.
- Investigated the role of endogenous and ectopic GAGE expression in peptide-induced cell death.
Main Results:
- Peptide#1, derived from the N-terminus of GAGE, effectively induced cell death in HeLa cells.
- GAGE-deficient cells (HEK293, fibroblasts) exhibited reduced sensitivity to Peptide#1.
- Endogenous or ectopic GAGE expression enhanced sensitivity to Peptide#1, indicating dominant active properties.
Conclusions:
- The N-terminal peptide of GAGE demonstrates selective cancer cell-killing activity.
- GAGE expression levels correlate with sensitivity to this novel peptide therapeutic.
- This GAGE-targeting peptide holds significant potential for targeted cancer therapy, sparing normal tissues.
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