Metformin impairs cisplatin resistance effects in A549 lung cancer cells through mTOR signaling and other metabolic pathways

Author(s):Show less -

Morelli, Ana Paula ^[1] ; Tortelli, Tharcisio Citrangulo Jr Jr ; Betim Pavan, Isadora Carolina ^{[1, 2]} ; Silva, Fernando Riback ^[2] ; Granato, Daniela Campos ^[3] ; Peruca, Guilherme Francisco ^[4] ; Pauletti, Bianca Alves ^[3] ; Domingues, Romenia Ramos ^[3] ; Neves Bezerra, Rosangela Maria ^[1] ; De Moura, Leandro Pereira ^[4] ; Paes Leme, Adriana Franco ^[3] ; Chammas, Roger ^{[5, 6]} ; Simabuco, Fernando Moreira ^[1]

Affiliation

^[1] Univ Estadual Campinas, Sch Appl Sci, Multidisciplinary Lab Food & Hlth, Rua Pedro Zaccaria 1300, BR-13484350 Limeira, SP - Brazil

^[2] Univ Estadual Campinas, Sch Pharmaceut Sci, Lab Signaling Mech, BR-13083871 Campinas, SP - Brazil

^[3] Brazilian Ctr Res Energy & Mat, Brazilian Biosci Natl Lab, BR-13083970 Campinas, SP - Brazil

^[4] Univ Estadual Campinas, Sch Appl Sci, Exercise Cell Biol Lab, BR-13484350 Limeira, SP - Brazil

^[5] Tortelli, Jr., Tharcisio Citrangulo Jr Jr, Univ Sao Paulo, Ctr Invest Translac Oncol, Dept Radiol & Oncol, Fac Med, BR-04021001 Sao Paulo, SP - Brazil

^[6] Tortelli, Jr., Tharcisio Citrangulo Jr Jr, Inst Canc Estado Sao Paulo, BR-04021001 Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: International Journal of Oncology; v. 58, n. 6 JUN 2021.
• Web of Science Citations: 0

Abstract

Lung cancer is the leading cause of cancer-associated death worldwide and exhibits intrinsic and acquired therapeutic resistance to cisplatin (CIS). The present study investigated the role of mTOR signaling and other signaling pathways after metformin (MET) treatment in control and cisplatin-resistant A549 cells, mapping pathways and possible targets involved in CIS sensitivity. MTT, flow cytometry, clonogenic assay, western blotting, proteomic analysis using the Stable Isotope Labeling by Amino acids in Cell culture (SILAC) approach and reverse transcription-quantitative PCR were performed. The results revealed that CIS treatment induced mTOR signaling pathway overactivation, and the mTOR status was restored by MET. MET and the mTOR inhibitor rapamycin (RAPA) decreased the viability in control and resistant cells, and decreased the cell size increase induced by CIS. In control cells, MET and RAPA decreased colony formation after 72 h and decreased IC50 values, potentiating the effects of CIS. Proteomics analysis revealed important pathways regulated by MET, including transcription, RNA processing and IL-12-mediated signaling. In CIS-resistant cells, MET regulated the apoptotic process, oxidative stress and G(2)/M transition. Annexin 4 (ANXA4) and superoxide dismutase 2 (SOD2), involved in apoptosis and oxidative stress, respectively, were chosen to validate the SILAC analysis and may represent potential therapeutic targets for lung cancer treatment. In conclusion, the chemosensitizing and antiproliferative effects of MET were associated with mTOR signaling and with potential novel targets, such as ANXA4 and SOD2, in human lung cancer cells. (AU)

• FAPESP's process: 16/02483-7 - Study of metformin effects in mTOR/S6Ks signal transduction pathway in lung cancer cells
• Grantee: Ana Paula Morelli
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 19/00607-9 - Characterization of molecular targets involved in chemotherapeutic resistance and tumor metabolism of lung cancer cells
• Grantee: Ana Paula Morelli
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 15/22814-5 - Cancer and heart: new paradigms of diagnosis and treatment
• Grantee: Carlos Eduardo Negrão
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 17/04269-5 - Proteomic analysis of A549 lung cancer cells treated with cisplatin and metformin
• Grantee: Ana Paula Morelli
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 15/16601-9 - Study of the relationship between NPM1 and NCL and different S6Ks isoforms
• Grantee: Fernando Riback Silva
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 18/14818-9 - Study of molecular targets important for the control of cancer metabolism: the mTOR/S6K pathway as a central role
• Grantee: Fernando Moreira Simabuco
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2
• FAPESP's process: 16/06457-0 - Leaves and stalks of beet (Beta vulgaris L.): characterization and effects of the antioxidant capacity in obese and dyslipidemic
• Grantee: Rosângela Maria Neves Bezerra
• Support Opportunities: Regular Research Grants
• FAPESP's process: 12/13558-7 - Molecular characterization of S6Ks in obesity and its associated diseases
• Grantee: Fernando Moreira Simabuco
• Support Opportunities: Research Grants - Young Investigators Grants