Lipoic acid decreases breast cancer cell proliferation by inhibiting IGF-1R via furin downregulation

被引:27
|
作者
Farhat, Diana [1 ,2 ,3 ,4 ]
Leon, Sophie [5 ]
Ghayad, Sandra E. [6 ]
Gadot, Nicolas [7 ]
Icard, Philippe [8 ,9 ]
Le Romancer, Muriel [1 ,2 ,3 ]
Hussein, Nader [4 ]
Lincet, Hubert [1 ,2 ,3 ,10 ]
机构
[1] Univ Lyon 1, Lyon, France
[2] CRCL, Inserm U1052, Lyon, France
[3] CRCL, CNRS, UMR5286, Lyon, France
[4] Lebanese Univ, Fac Sci Canc Biol Stem Cells & Mol Immunol, Hadath Beirut, Lebanon
[5] Ctr Leon Berard, INCa DGOS Inserm 12563, SIRIC LYriCAN, Plateforme Ex Vivo,Dept Rech Translat & Innovat, Lyon, France
[6] Lebanese Univ, Fac Sci 2, Dept Biol, Fanar, Lebanon
[7] Ctr Leon Berard, Dept Rech Translat & Innovat, Plateforme Anatomopathol Rech, Lyon, France
[8] Normandie Univ, Unite Rech BioTICLA INSERM U 119, CHU Caen Normandie, UNICAEN, F-14000 Caen, France
[9] Hop Univ Paris Ctr, Serv Chirurg Thorac, Hop Cochin, Paris, France
[10] ISPB, Fac Pharm, Lyon, France
关键词
NF-KAPPA-B; GROWTH-FACTORS; PHOSPHATIDYLINOSITOL; 3-KINASE; INSULIN-RECEPTOR; IN-VITRO; PI3K/AKT/MTOR; APOPTOSIS; PATHWAYS; KINASE; ACTIVATION;
D O I
10.1038/s41416-020-0729-6
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background Breast cancer is the second most common cancer in the world. Despite advances in therapies, the mechanisms of resistance remain the underlying cause of morbidity and mortality. Lipoic acid (LA) is an antioxidant and essential cofactor in oxidative metabolism. Its potential therapeutic effects have been well documented, but its mechanisms of action (MOA) are not fully understood. Methods The aim of this study is to validate the inhibitory LA effect on the proliferation of various breast cancer cell lines and to investigate the MOA that may be involved in this process. We tested LA effects by ex vivo studies on fresh human mammary tumour samples. Results We demonstrate that LA inhibits the proliferation and Akt and ERK signalling pathways of several breast cancer cells. While searching for upstream dysregulations, we discovered the loss of expression of IGF-1R upon exposure to LA. This decrease is due to the downregulation of the convertase, furin, which is implicated in the maturation of IGF-1R. Moreover, ex vivo studies on human tumour samples showed that LA significantly decreases the expression of the proliferation marker Ki67. Conclusion LA exerts its anti-proliferative effect by inhibiting the maturation of IGF-1R via the downregulation of furin.
引用
收藏
页码:885 / 894
页数:10
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