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Biochem Biophys Res Commun. 2017 Dec 9;494(1-2):325-331. doi: 10.1016/j.bbrc.2017.10.030. Epub 2017 Oct 7.

α-Lipoic acid inhibits human lung cancer cell proliferation through Grb2-mediated EGFR downregulation.

Author information

1
Shenzhen Tumor Immuno-gene Therapy Clinical Application Engineering Lab, Biobank of Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, PR China; Institute of Immunology of Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510060, Guangdong, PR China.
2
Shenzhen Tumor Immuno-gene Therapy Clinical Application Engineering Lab, Biobank of Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, PR China; Department of Graduate School, Guangzhou Medical University, Guangzhou 511436, PR China.
3
Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen 518035, PR China.
4
Shenzhen Tumor Immuno-gene Therapy Clinical Application Engineering Lab, Biobank of Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, PR China.
5
Shenzhen Tumor Immuno-gene Therapy Clinical Application Engineering Lab, Biobank of Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, PR China. Electronic address: xiaojuansun1978@163.com.

Abstract

BACKGROUND:

Alpha lipoic acid (α -LA) is a naturally occurring antioxidant and metabolic enzyme co-factor. Recently, α -LA has been reported to inhibit the growth of various cancer cells, but the precise signaling pathways that mediate the effects of α -LA on non-small cell lung cancer (NSCLC) development remain unclear.

METHODS:

The CCK-8 assay was used to assess cell proliferation in NSCLC cell lines after α -LA treatment. The expression of growth factor receptor-bound protein 2 (Grb2), cyclin-dependent kinase (CDK)-2, CDK4, CDK6, Cyclin D3, Cyclin E1, Ras, c-Raf, epidermal growth factor receptor (EGFR), ERK1/2 and activated EGFR and ERK1/2 was evaluated by western blotting. Grb2 levels were restored in α-LA-treated cells by transfection of a plasmid carrying Grb2 and were reduced in NSCLC cells via specific siRNA-mediated knockdown.

RESULTS:

α -LA dramatically decreased NSCLC cell proliferation by downregulating Grb2; in contrast, Grb2 overexpression significantly prevented α-LA-induced decrease in cell growth in vitro. Western blot analysis indicated that α-LA decreased the levels of phospho-EGFR, CDK2/4/6, Cyclins D3 and E1, which are associated with the inhibition of G1/S-phase transition. Additional experiments indicated that Grb2 inhibition partially abolished EGF-induced phospho-EGFR and phospho-ERK1/2 activity. In addition, α-LA exerted greater inhibitory effects than gefitinib on NSCLC cells by preventing EGF-induced EGFR activation.

CONCLUSION:

For the first time, these findings provide the first evidence that α-LA inhibits cell proliferation through Grb2 by suppressing EGFR phosphorylation and that MAPK/ERK is involved in this pathway.

KEYWORDS:

Cell proliferation; EGFR; Grb2; NSCLC; α-lipoic acid

PMID:
28993193
DOI:
10.1016/j.bbrc.2017.10.030
[Indexed for MEDLINE]

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