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Published on: May 14, 2016
The Selectivity for Tumor Cells of Nuclear-Directed Cytotoxic RNases Is Mediated by the Nuclear/Cytoplasmic
Glòria García-Galindo1, Jessica Castro1,2, Jesús Matés1,2
1Laboratori d'Enginyeria de Proteïnes, Departament de Biologia, Facultat de Ciències, Universitat de Girona, Campus de Montilivi, Maria Aurèlia Capmany 40, 17003 Girona, Spain.
Abstract:
Although single targeted anti-cancer drugs are envisaged as safer treatments because they do not affect normal cells, cancer is a very complex disease to be eradicated with a single targeted drug. Alternatively, multi-targeted drugs may be more effective and the tumor cells may be less prone to develop drug resistance although these drugs may be less specific for cancer cells. We have previously developed a new strategy to endow human pancreatic ribonuclease with antitumor action by introducing in its sequence a non-classical nuclear localization signal. These engineered proteins cleave multiple species of nuclear RNA promoting apoptosis of tumor cells. Interestingly, these enzymes, on ovarian cancer cells, affect the expression of multiple genes implicated in metabolic and signaling pathways that are critic for the development of cancer. Since most of these targeted pathways are not highly relevant for non-proliferating cells, we envisioned the possibility that nuclear directed-ribonucleases were specific for tumor cells. Here, we show that these enzymes are much more cytotoxic for tumor cells in vitro. Although the mechanism of selectivity of NLSPE5 is not fully understood, herein we show that p27KIP1 displays an important role on the higher resistance of non-tumor cells to these ribonucleases.
Insights
Engineered ribonucleases target cancer cells by cleaving nuclear RNA, inducing apoptosis. Non-tumor cells show resistance, partly due to p27KIP1, suggesting targeted cancer therapy potential.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Cancer complexity necessitates multi-targeted therapies over single-drug approaches.
- Engineered human pancreatic ribonuclease with a nuclear localization signal (NLS) demonstrates antitumor activity.
- Targeting nuclear RNA in tumor cells offers a novel therapeutic strategy.
Purpose of the Study:
- To evaluate the cytotoxic effects and selectivity of engineered ribonucleases on tumor cells.
- To investigate the role of p27KIP1 in the resistance of non-tumor cells to these agents.
Main Methods:
- Engineering human pancreatic ribonuclease with a non-classical NLS.
- In vitro cytotoxicity assays on tumor and non-tumor cells.
- Analysis of gene expression changes in ovarian cancer cells.
- Investigating the role of p27KIP1 in cellular resistance.
Main Results:
- Engineered ribonucleases exhibit significant cytotoxicity towards tumor cells in vitro.
- These enzymes affect multiple cancer-critical metabolic and signaling pathways.
- Non-tumor cells demonstrate higher resistance to the engineered ribonucleases.
- p27KIP1 plays a role in the resistance of non-tumor cells.
Conclusions:
- Engineered nuclear-directed ribonucleases show promise as specific anti-cancer agents.
- The differential cytotoxicity suggests potential for targeted cancer therapy.
- p27KIP1 is implicated in the selective resistance of normal cells, warranting further investigation.
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