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

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Arquivos
art_MORELLI_Metformin_impairs_cisplatin_resistance_effects_in_A549_lung_2021.PDF (2.8 MB)
Citações na Scopus
15
Tipo de produção
article
Data de publicação
2021
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
SPANDIDOS PUBL LTD
Autores
MORELLI, Ana Paula
PAVAN, Isadora Carolina Betim
SILVA, Fernando Riback
GRANATO, Daniela Campos
PERUCA, Guilherme Francisco
PAULETTI, Bianca Alves
DOMINGUES, Romenia Ramos
BEZERRA, Rosangela Maria Neves
MOURA, Leandro Pereira De
Citação
INTERNATIONAL JOURNAL OF ONCOLOGY, v.58, n.6, article ID 28, 15p, 2021
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
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.
Palavras-chave
lung cancer, cisplatin resistance, metformin, mTOR, proteomics
URI
https://observatorio.fm.usp.br/handle/OPI/40629
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Coleções
Artigos e Materiais de Revistas Científicas - FM/MDR
Artigos e Materiais de Revistas Científicas - HC/ICESP
Artigos e Materiais de Revistas Científicas - LIM/24
Artigos e Materiais de Revistas Científicas - ODS/03