The selective inhibition of nuclear PKCζ restores the effectiveness of chemotherapeutic agents in chemoresistant cells
| Autor: | Carlotta Giorgi, Rosario Rizzuto, Alessandro Rimessi, Erika Zecchini, Sara Leo, Paolo Pinton, Roberta Siviero |
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| Rok vydání: | 2012 |
| Předmět: |
Antineoplastic Agents
Apoptosis Biology medicine.disease_cause Transfection Report medicine Cytotoxic T cell Humans Molecular Biology Protein kinase C Protein Kinase C Cell Biology Hydrogen Peroxide 3. Good health Cell biology Oxidative Stress Doxorubicin Drug Resistance Neoplasm Cancer cell Signal transduction Carcinogenesis Reactive Oxygen Species Intracellular Developmental Biology HeLa Cells |
| Zdroj: | Cell Cycle; Vol 11 |
| Popis: | The atypical protein kinase C (PKC) isoform zeta (PKCζ) has been implicated in the intracellular transduction of mitogenic and apoptotic signals by acting on different signaling pathways. The key role of these processes in tumorigenesis suggests a possible involvement of PKCζ in this event. PKCζ is activated by cytotoxic treatments, inhibits apoptotic cell death and reduces the sensitivity of cancer cells to chemotherapeutic agents. Here, using pharmacological and DNA recombinant approaches, we show that oxidative stress triggers nuclear translocation of PKCζ and induces resistance to apoptotic agents. Accordingly, chemoresistant cells show accumulation of PKCζ within the nucleus, and a nuclear-targeted PKCζ transfected in tumor cells decreases sensitivity to apoptosis. We thus developed a novel recombinant protein capable of selectively inhibiting the nuclear fraction of PKCζ that restored the susceptibility to apoptosis in cells in which PKCζ was enriched in the nuclear fraction, including chemoresistant cells. These findings establish the importance of PKCζ as a possible target to increase the effectiveness of anticancer therapies and highlight potential sites of intervention. |
| Databáze: | OpenAIRE |
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