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A human ribonuclease induces apoptosis associated with p21WAF1/CIP1 induction and JNK inactivation
- Source :
- BMC Cancer, Recercat. Dipósit de la Recerca de Catalunya, instname, BMC Cancer, 2011, vol. 11, núm. 9, Articles publicats (D-B), DUGiDocs – Universitat de Girona, BMC Cancer, Vol 11, Iss 1, p 9 (2011), Dipòsit Digital de Documents de la UAB, Universitat Autònoma de Barcelona
- Publication Year :
- 2018
- Publisher :
- BioMed Central, 2018.
-
Abstract
- Background Ribonucleases are promising agents for use in anticancer therapy. Among the different ribonucleases described to be cytotoxic, a paradigmatic example is onconase which manifests cytotoxic and cytostatic effects, presents synergism with several kinds of anticancer drugs and is currently in phase II/III of its clinical trial as an anticancer drug against different types of cancer. The mechanism of cytotoxicity of PE5, a variant of human pancreatic ribonuclease carrying a nuclear localization signal, has been investigated and compared to that of onconase. Methods Cytotoxicity was measured by the MTT method and by the tripan blue exclusion assay. Apoptosis was assessed by flow cytometry, caspase enzymatic detection and confocal microscopy. Cell cycle phase analysis was performed by flow cytometry. The expression of different proteins was analyzed by western blot. Results We show that the cytotoxicity of PE5 is produced through apoptosis, that it does not require the proapoptotic activity of p53 and is not prevented by the multiple drug resistance phenotype. We also show that PE5 and onconase induce cell death at the same extent although the latter is also able to arrest the cell growth. We have compared the cytotoxic effects of both ribonucleases in the NCI/ADR-RES cell line by measuring their effects on the cell cycle, on the activation of different caspases and on the expression of different apoptosis- and cell cycle-related proteins. PE5 increases the number of cells in S and G2/M cell cycle phases, which is accompanied by the increased expression of cyclin E and p21WAF1/CIP1 together with the underphosphorylation of p46 forms of JNK. Citotoxicity of onconase in this cell line does not alter the cell cycle phase distribution and it is accompanied by a decreased expression of XIAP Conclusions We conclude that PE5 kills the cells through apoptosis associated with the p21WAF1/CIP1 induction and the inactivation of JNK. This mechanism is significantly different from that found for onconase.
- Subjects :
- Cyclin-Dependent Kinase Inhibitor p21
Programmed cell death
Cancer Research
Cell Survival
Cell
Blotting, Western
Apoptosis
Biology
lcsh:RC254-282
Cancer -- Treatment
Cell cycle phase
Inhibitory Concentration 50
Ribonucleases
Cell Line, Tumor
Cyclin E
medicine
Genetics
Escherichia coli
Cytotoxic T cell
Humans
Cyclin D1
Mitogen-Activated Protein Kinase 8
Dose-Response Relationship, Drug
Cell growth
Cell Cycle
Cell cycle
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Recombinant Proteins
XIAP
Cell biology
Enzyme Activation
medicine.anatomical_structure
Oncology
Caspases
Càncer -- Tractament
HeLa Cells
Research Article
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- BMC Cancer, Recercat. Dipósit de la Recerca de Catalunya, instname, BMC Cancer, 2011, vol. 11, núm. 9, Articles publicats (D-B), DUGiDocs – Universitat de Girona, BMC Cancer, Vol 11, Iss 1, p 9 (2011), Dipòsit Digital de Documents de la UAB, Universitat Autònoma de Barcelona
- Accession number :
- edsair.doi.dedup.....b8d6fdf8f268298f38500125257aed7e