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Evaluation of PAFR activation in the survival response and chemoresistance of tumor cells exposed to hypoxia

Grant number: 16/26255-3
Support type:Scholarships abroad - Research Internship - Master's degree
Effective date (Start): March 01, 2017
Effective date (End): August 31, 2017
Field of knowledge:Biological Sciences - Biology
Principal researcher:Roger Chammas
Grantee:Mayara Dauria Jacomassi
Supervisor abroad: Adrian Llewellyn Harris
Home Institution: Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira (ICESP). Coordenadoria de Serviços de Saúde (CSS). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Research place: University of Oxford, England  
Associated to the scholarship:15/26262-7 - Involvement of PAFR activation during chemotherapy in the melanoma repopulation phenomenon, BP.MS

Abstract

Metastatic melanoma has been considered a clinical challenge due to its notorious chemoresistance. The understanding of molecular and cellular events that contributes to melanoma chemoresistance is important to improve current therapies and prevent tumor recurrence. Previous in vivo studies from our group showed that PAFR activation favors melanoma growth by protecting to cisplatin-induced cell death. Furthermore, the expression of PAFR was increased in hypoxic tumor areas. It is already known that tumor cells undergoing hypoxia are more resistant to treatment and that it might contribute to tumor recurrence. Therefore, we intend to evaluate whether PAFR activation is involved in chemoresistance under hypoxia. Human melanoma cell line SKmel 37 was exposed to hypoxia followed by reoxygenation in the presence of PAFR antagonist, WEB 2086 under cisplatin treatment. Cell death was assessed by propidium iodide staining and flow cytometric analyses. We observed that cells exposed to hypoxia were more resistant to cisplatin-induced cell death than cells in normoxia. Moreover, PAFR blockage with WEB 2086 sensitized cells in hypoxia and the combined treatment was synergic. We also evaluated PAFR protein levels by Western Blot. Interestingly, neither hypoxia nor cisplatin alter PAFR levels. Besides explore this phenomenon in other cell lines, using appropriate hypoxia workstations, we seek to evaluate the generation of PAFR ligands after hypoxia and/or cisplatin treatment by mass spectrometry. We are also interested to explore the survival mechanism triggered by PAFR activation under these experimental conditions and we hypothesize that autophagy can be related somehow. Moreover, if PAFR activation hasan impact on cisplatin resistance under hypoxia, we will use CRISPR/Cas9 system todelete PAFR gene and perform in vitro and in vivo experiments. The involvement of PAFR in chemoresistance under hypoxia could lead to the development of a new therapy targeting this receptor (for example, hypoxia-activated pro-drugs) and the conventional treatment with cisplatin could be improved when associated with drugs targeting PAFR.

News published in Agência FAPESP Newsletter about the scholarship: