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Metformin impairs cisplatin resistance effects in A549 lung cancer cells through mTOR signaling and other metabolic pathways
- Source :
- International Journal of Oncology
- Publication Year :
- 2021
- Publisher :
- D.A. Spandidos, 2021.
-
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 G2/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.
- Subjects :
- Cancer Research
Lung Neoplasms
Cell
SOD2
Biology
medicine.disease_cause
proteomics
Stable isotope labeling by amino acids in cell culture
Carcinoma, Non-Small-Cell Lung
Antineoplastic Combined Chemotherapy Protocols
medicine
Humans
PI3K/AKT/mTOR pathway
A549 cell
TOR Serine-Threonine Kinases
Articles
Cell cycle
Metformin
Gene Expression Regulation, Neoplastic
lung cancer
medicine.anatomical_structure
Oncology
Apoptosis
A549 Cells
Drug Resistance, Neoplasm
Cancer research
mTOR
cisplatin resistance
Cisplatin
Oxidative stress
Metabolic Networks and Pathways
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 17912423 and 10196439
- Volume :
- 58
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- International Journal of Oncology
- Accession number :
- edsair.doi.dedup.....85dbb6256b43fc7ae02b36ac2e850dc1