Lipoic acid-induced oxidative stress abrogates IGF-1R maturation by inhibiting the CREB/furin axis in breast cancer cell lines

• Published in: Oncogene 2020-04, Vol.39 (17), p.3604-3610
• Main Authors: Farhat, Diana, Ghayad, Sandra E., Icard, Philippe, Le Romancer, Muriel, Hussein, Nader, Lincet, Hubert
• Format: Article
• Language: English
• Subjects: 14/19; 14/34; 45/77; 631/67; 631/80; 82/80; 96/109; Apoptosis; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Brief Communication; Cancer; Care and treatment; Cell Biology; Cell cycle; Cell growth; Cell proliferation; Cell viability; Cellular signal transduction; Cyclic AMP response element-binding protein; Cyclic AMP Response Element-Binding Protein - metabolism; Development and progression; Estrogen receptors; Female; Furin; Furin - metabolism; Gene expression; Genetic aspects; Growth factors; Health aspects; Human Genetics; Humans; Insulin-like growth factors; Internal Medicine; Kinases; Life Sciences; Lipoic acid; MCF-7 Cells; Medicine; Medicine & Public Health; Mesenchyme; Neoplasm Proteins - metabolism; Oncology; Oxidants; Oxidative stress; Oxidative Stress - drug effects; Proprotein convertases; Reactive oxygen species; Receptor, IGF Type 1 - metabolism; Thioctic Acid - pharmacology; Tumor cell lines
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-020-1211-x

The beneficial effects of lipoic acid (LA) in cancer treatment have been well documented in the last decade. Indeed, LA exerts crucial antiproliferative effects by reducing breast cancer cell viability, cell cycle progression and the epithelial-to-mesenchymal transition (EMT). However, the mechanisms of action (MOA) underlying these antiproliferative effects remain to be elucidated. Recently, we demonstrated that LA decreases breast cancer cell proliferation by inhibiting IGF-1R maturation via the downregulation of the proprotein convertase furin. The aim of the present study was to investigate the MOA by which LA inhibits furin expression in estrogen receptor α (ERα) (+) and (−) breast cancer cell lines. We unveil that LA exerts a pro-oxidant effect on these cell lines, the resulting reactive oxygen species (ROS) generated being responsible for the reduction in the expression of the major (CREB) protein. This transcription factor is overexpressed in many types of cancers and regulates the expression of furin in breast cancer cells independently of ERα, as evidenced herein by the inhibition of furin expression following CREB silencing. Consequently, our findings expose for the first time the complete MOA of LA via the CREB/furin axis leading to inhibition of breast cancer cell proliferation.