Caenorhabditis elegans as animal model to investigate the cellular mechanism of resistance for the chemotherapeutic agent cisplatin
In the last three decades, cisplatin has been one of the most widely prescribed drugs being an effective treatment for many cancer types. Despite its effectiveness, many patients are intrinsically resistant to cisplatin-based therapies and an important fraction of tumors eventually develop chemoresi...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2016 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/397787 |
| Acceso en línea: | http://hdl.handle.net/10803/397787 |
| Access Level: | acceso abierto |
| Palabra clave: | Cisplatí Cisplatino Cisplatin Quimioteràpia del càncer Quimioterapia del cancer Cancer chemotherapy Resistència als medicaments Resistencia a los medicamentos Drug resistance Ciències Experimentals i Matemàtiques 575 |
| Sumario: | In the last three decades, cisplatin has been one of the most widely prescribed drugs being an effective treatment for many cancer types. Despite its effectiveness, many patients are intrinsically resistant to cisplatin-based therapies and an important fraction of tumors eventually develop chemoresistance to this agent. In this study we consolidate C. elegans as a pluricellular model (I) to better understand the biological response to cisplatin-based chemotherapy to finally to map cellular pathways capable of modulating the response to cisplatin and (II) to functionally validate candidate genes involved in the such response to cisplatin. We discover that cisplatin-induced damage provokes in worms specific cell-type apoptotic activation and induces a systemic response promoting the activation of a set of redox-stress responsive genes whose transcription is mediated by the evolutionary conserved Insulin-IGF-like receptor signaling pathway (IIS) transcription factors SKN-1/Nrf2 and DAF-16/FOXO. In addition, altering both IIS-pathway-related genes and some of their targets leads to modify the response to cisplatin. Accordingly, this study demonstrates the importance of redox homeostasis in the resistance to cisplatin, and the central role of Nrf2/SKN-1 and FOXO/DAF-16 as modulators of cisplatin resistance acquisition through this mechanism, which is conserved from worms to mammals. We also demonstrated, after an RNAi based approach using C. elegans, that several genes present at the 9q32-q33.1 human region, such as the glucosyl ceramide synthase or the copper transporter, were able to individually alter the response to cisplatin. Moreover, we demonstrated the relevance of the glucosylceramide synthase activity as a biological mechanism that mediate tumor cell protection against cisplatin exposure in tumorgraft models, highlighting the relevance of targeting glucosylceramide synthase as a novel approach to resensitize tumors to cisplatin. This confirms the translational value of C. elegans in cisplatin-based research, which could fill the gap between in vitro and preclinical studies. |
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