Effect of RECK Protein on Sensitization of HPV-transformed Cells to antineoplastic therapies

• Grant number: 24/14442-0
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: June 01, 2025
• End date: April 30, 2028
• Field of knowledge: Biological Sciences - Microbiology
• Principal Investigator: Enrique Mario Boccardo Pierulivo
• Grantee: Adriana García Forero
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Human papillomavirus (HPV)-associated malignancies, mainly cervical cancer, are a global public health problem, especially in developing regions such as Latin America. Currently, the main treatments for advanced cervical cancer are radiotherapy combined with cisplatin-based chemotherapy. However, there is a high rate of relapse caused by the resistance developed by tumor cells. One of the molecular mechanisms that mediate tumor cell resistance is the altered expression of DNA repair proteins. Previous studies from our laboratory found that some proteins involved in DNA repair, namely ATM, BRCA1, CHK2, TREX1 and HMGB1, are critical for the survival and oncogenic potential of HPV-transformed cells. Besides, we reported that the tumor suppressor protein RECK is consistently down-regulated in HPV-associated tumors and that its' over-expression reduces the tumorigenic potential of HPV-transformed cell lines. Interestingly, it was reported that HMGB1 is involved in RECK downregulation and that RECK expression inhibits DNA repair, causes stress in the endoplasmic reticulum and induces hypersensitivity to chemotherapeutic agents. However, the functional relationship between DNA repair, endoplasmic reticulum stress and RECK has not been addressed in HPV-associated pathologies. Therefore, the aim of our project is to investigate the effect of RECK protein on sensitization of HPV-transformed cells to chemotherapeutic and radiomimetic agents and get insights on the molecular mechanisms involved. For this purpose, cell lines that super-express RECK will be treated with chemotherapeutic and radiomimetic agents and their viability, proliferative, migration and invasion capacities will be investigated. Besides, in these cells, factors involved in DNA repair, fundamental for HPV-transformed cell viability will be silenced or inhibited, the DNA repair capacity will be determined. Finally, we will investigate the molecular pathways by which RECK sensitizes treated cells through the analysis of expression profile and activity of DNA repair and endoplasmic reticulum stress associated factors.