Metformin induces apoptotic cytotoxicity depending on AMPK/PKA/GSK-3β-mediated c-FLIPL degradation in non-small cell lung cancer
Received 5 July 2018
Accepted for publication 3 December 2018
Published 11 January 2019 Volume 2019:11 Pages 681—689
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Andrew Yee
Peer reviewer comments 2
Editor who approved publication: Dr Ahmet Emre Eskazan
Zhuang Luo,1,* Tingting Zhu,2,* Wei Luo,3,* Yuanyuan Lv,1 Liyan Zhang,1 Chu Wang,1 Min Li,1 Wenjuan Wu,4 Shaoqing Shi1
1Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, People’s Republic of China; 2Department of Dermatology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, People’s Republic of China; 3Department of Respiratory Medicine, The People’s Hospital of Leshan, Leshan, Sichuan 640000, People’s Republic of China; 4Department of Dermatology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, People’s Republic of China
*These authors contributed equally to this work
Background: Metformin, a first-line antidiabetic drug, has recently been reported with anticancer activities in various cancers; however, the underlying mechanisms remain elusive. The aim of the present study was to investigate the role of cellular FADD-like IL-1β-converting enzyme (FLICE)-inhibitory protein large (c-FLIPL) in metformin-induced anticancer activity in non-small cell lung cancer (NSCLC) in vitro.
Materials and methods: Cell viability was measured by MTT assay. Quantitative real-time PCR was carried out to detect the level of mRNA of related genes. The expression of related proteins was detected by Western blot. siRNA was used to silence the expression of targeted proteins.
Results: Metformin significantly suppressed proliferation of both A549 and H460 cells in a dose-dependent manner. Mechanistic studies suggested that metformin killed NSCLC cells by inducing apoptotic cell death. Moreover, metformin greatly inhibited c-FLIPL expression and then promoted its degradation. Furthermore, metformin significantly activated Adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) and its downstream glycogen synthase kinase 3beta (GSK-3β), block the expression of AMPK, and GSK-3β with siRNA partially reversed metformin-induced cytotoxicity and restored the expression of c-FLIPL in lung cancer cells. Metformin also suppressed the activity of AMPK downstream protein kinase A (PKA), PKA activators, both 8-Br-cAMP and forskolin, greatly increased c-FLIPL expression in NSCLC cells.
Conclusion: This study provided evidence that metformin killed NSCLC cells through AMPK/PKA/GSK-3β axis-mediated c-FLIPL degradation.
Keywords: non-small cell lung cancer, c-FLIPL, AMPK, GSK-3β, PKA
This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.Download Article [PDF] View Full Text [HTML][Machine readable]