期刊
INTERNATIONAL JOURNAL OF ONCOLOGY
卷 58, 期 6, 页码 -出版社
SPANDIDOS PUBL LTD
DOI: 10.3892/ijo.2021.5208
关键词
lung cancer; cisplatin resistance; metformin; mTOR; proteomics
类别
资金
- Sao Paulo Research Foundation (FAPESP) [2012/13558-7, 2018/14818-9, 2016/06457-0, 2015/22814-5, 2016/02483-7, 2017/04269-5, 2019/00607-9, 2015/003111, 2015/16601-9]
- National Council for Scientific and Technological Development [447553/2014-3]
This study investigated the role of mTOR signaling after MET treatment in lung cancer cells, revealing the mechanisms underlying MET's chemosensitizing effects and potential novel therapeutic targets. MET was found to regulate pathways related to apoptosis, oxidative stress, and cell cycle progression in CIS-resistant cells, highlighting the potential of ANXA4 and SOD2 as therapeutic targets for lung cancer treatment.
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据