| Grant number: | 19/00607-9 |
| Support type: | Scholarships in Brazil - Master |
| Effective date (Start): | May 01, 2019 |
| Effective date (End): | April 30, 2021 |
| Field of knowledge: | Biological Sciences - Biochemistry - Molecular Biology |
| Principal researcher: | Fernando Moreira Simabuco |
| Grantee: | Ana Paula Morelli |
| Home Institution: | Faculdade de Ciências Aplicadas (FCA). Universidade Estadual de Campinas (UNICAMP). Limeira , SP, Brazil |
Abstract Despite the development of new therapies and early diagnosis, cancer is still an extremely important disease in terms of mortality, especially lung cancer which accounts for 30% of overall mortality. The therapy challenges involve the molecular complexity from the onset of the disease to its progression, emphasizing the demand for a better understanding of cancer metabolism. Although cisplatin is the treatment of choice for lung cancer, the treatment involves many side effects and a limited long-term efficacy by the profile of innate or acquired drug resistance that the tumors exhibit. In previous data, we have shown through a proteomic analysis that treatment with cisplatin increases the expression of possible targets associated with chemotherapeutic resistance, such as STAT3 and PCNA, and that treatment with metformin, which sensitizes cells to cisplatin treatment, is able to reduce the expression and activity of STAT3. In addition, our data characterized the role of mTOR/S6Ks pathway in maintenance of the cisplatin-acquired resistance phenotype and the sensitivity to new exposures following treatment with rapamycin, an inhibitor of mTOR pathway. Giving the success of the CRISPR/Cas9 technique in the specific genome edition, this project aims to genetically modify A549 lung cancer cells, establishing stable cell knockout for STAT3 (STAT3 -/-), PCNA (PCNA-/-) and both (STAT3-/-; PCNA-/-), characterizing specifically the role of these targets in the resistance acquired to cisplatin, exposure to chemotherapy and sensitivity to pre-exposure and treatment with other drugs, such as rapamycin and metformin. Using other molecular biology tools, we intend to overexpress these genes and analyze the same effects. In addition, the project aims to characterize the role of STAT3 and PCNA in lung cancer metabolism through functional assays of migration, cell proliferation, clonogenic ability and cell viability. (AU) | |