Characterization of molecular targets involved in chemotherapeutic resistance and tumor metabolism of lung cancer cells

• Grant number: 19/00607-9
• Support Opportunities: 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 Investigator: Fernando Moreira Simabuco
• Grantee: Ana Paula Morelli
• Host 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)

Scientific publications

(6)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MORELLI, ANA PAULA; TORTELLI, THARCISIO CITRANGULO JR JR; BETIM PAVAN, ISADORA CAROLINA; SILVA, FERNANDO RIBACK; GRANATO, DANIELA CAMPOS; PERUCA, GUILHERME FRANCISCO; PAULETTI, BIANCA ALVES; DOMINGUES, ROMENIA RAMOS; NEVES BEZERRA, ROSANGELA MARIA; DE MOURA, LEANDRO PEREIRA; et al. Metformin impairs cisplatin resistance effects in A549 lung cancer cells through mTOR signaling and other metabolic pathways. International Journal of Oncology, v. 58, n. 6, JUN 2021. (16/02483-7, 19/00607-9, 15/22814-5, 17/04269-5, 15/16601-9, 18/14818-9, 16/06457-0, 12/13558-7)

PONTE, LUIS GUSTAVO SABOIA; PAVAN, ISADORA CAROLINA BETIM; MANCINI, MARIANA CAMARGO SILVA; DA SILVA, LUIZ GUILHERME SALVINO; MORELLI, ANA PAULA; SEVERINO, MATHEUS BRANDEMARTE; BEZERRA, ROSANGELA MARIA NEVES; SIMABUCO, FERNANDO MOREIRA. The Hallmarks of Flavonoids in Cancer. Molecules, v. 26, n. 7, APR 2021. (18/08391-2, 19/00607-9, 19/25582-9, 18/14818-9)

ROMERO, STEFHANI ANDRIOLI; BETIM PAVAN, ISADORA CAROLINA; MORELLI, ANA PAULA; SILVA MANCINI, MARIANA CAMARGO; SALVINO DA SILVA, LUIZ GUILHERME; FAGUNDES, ISABELLA; ROCHA SILVA, CAYO HENRIQUE; SABOIA PONTE, LUIS GUSTAVO; ROSTAGNO, MAURICIO ARIEL; NEVES BEZERRA, ROSANGELA MARIA; et al. Anticancer effects of root and beet leaf extracts (Beta vulgaris L.) in cervical cancer cells (HeLa). Phytotherapy Research, v. 35, n. 11, SEP 2021. (18/14818-9, 16/06457-0, 19/25582-9, 15/00311-1, 19/00607-9, 19/13848-4)

MORELLI, ANA PAULA; TORTELLI JR, THARCISIO CITRANGULO; SILVA MANCINI, MARIANA CAMARGO; BETIM PAVAN, ISADORA CAROLINA; SALVINO SILVA, LUIZ GUILHERME; SEVERINO, MATHEUS BRANDEMARTE; GRANATO, DANIELA CAMPOS; PESTANA, NATHALIE FORTES; SABOIA PONTE, LUIS GUSTAVO; PERUCA, GUILHERME FRANCISCO; et al. TAT3 contributes to cisplatin resistance, modulating EMT markers, and the mTOR signaling in lung adenocarcinom. Neoplasia, v. 23, n. 10, p. 1048-1058, OCT 2021. (19/25582-9, 15/22814-5, 15/00311-1, 18/14818-9, 19/00607-9, 20/09527-5)

SILVA MANCINI, MARIANA CAMARGO; SABOIA PONTE, LUIS GUSTAVO; ROCHA SILVA, CAYO HENRIQUE; FAGUNDES, ISABELLA; BETIM PAVAN, ISADORA CAROLINA; ROMEIRO, STEFHANI ANDRIOLI; SALVINO DA SILVA, LUIZ GUILHERME; MORELLI, ANA PAULA; ROSTAGNO, MAURICIO ARIEL; SIMABUCO, FERNANDO MOREIRA; et al. Beetroot and leaf extracts present protective effects against prostate cancer cells, inhibiting cell proliferation, migration, and growth signaling pathways. Phytotherapy Research, JUN 2021. (18/14818-9, 16/06457-0, 19/25582-9, 15/00311-1, 19/00607-9, 19/13848-4)

SILVA MANCINI, MARIANA CAMARGO; SABOIA PONTE, LUIS GUSTAVO; ROCHA SILVA, CAYO HENRIQUE; FAGUNDES, ISABELLA; BETIM PAVAN, ISADORA CAROLINA; ROMEIRO, STEFHANI ANDRIOLI; SALVINO DA SILVA, LUIZ GUILHERME; MORELLI, ANA PAULA; ROSTAGNO, MAURICIO ARIEL; SIMABUCO, FERNANDO MOREIRA; et al. Beetroot and leaf extracts present protective effects against prostate cancer cells, inhibiting cell proliferation, migration, and growth signaling pathways. Phytotherapy Research, v. 35, n. 9, p. 5241-5258, SEP 2021. (19/13848-4, 18/14818-9, 16/06457-0, 15/00311-1, 19/25582-9, 19/00607-9)