Regulation of monoamine oxidase A (MAO-A) expression, activity and function in IL-13-stimulated monocytes and A549 lung carcinoma cells.
J Biol Chem. 2018 Jul 18;:
Authors: Dhabal S, Das P, Biswas P, Kumari P, Yakubenko VP, Kundu S, Cathcart MK, Kundu M, Biswas K, Bhattacharjee A
Monoamine oxidase A (MAO-A) is a mitochondrial flavoenzyme implicated in the pathogenesis of atherosclerosis and inflammation and also in many neurological disorders. MAO-A also has been reported as a potential therapeutic target in prostate cancer. However, the regulatory mechanisms controlling cytokine-induced MAO-A expression in immune or cancer cells remain to be identified. Here, we show that MAO-A expression is co-induced with 15-lipoxygenase (15-LO) in interleukin 13 (IL-13)-activated primary human monocytes and A549 non-small cell lung carcinoma cells. We present evidence that MAO-A gene expression and activity are regulated by signal transducer and activator of transcription 1, 3 and 6 (STAT1, STAT3 and STAT6), early growth response 1 (EGR1) and cAMP-responsive element-binding protein (CREB), the same transcription factors that control IL-13-dependent 15-LO expression. We further established that in both primary monocytes and in A549 cells, IL-13-stimulated MAO-A expression, activity and function are directly governed by 15-LO. In contrast, IL-13-driven expression and activity of MAO-A was 15-LO-independent in U937 promonocytic cells. Furthermore, we demonstrate that the 15-LO-dependent transcriptional regulation of MAO-A in response to IL-13 stimulation in monocytes and in A549 cells is mediated by peroxisome proliferator-activated receptor g (PPARg) and that STAT6 plays a crucial role in facilitating the transcriptional activity of PPARg. We further report that the IL-13-STAT6-15-LO-PPARg axis is critical for MAO-A expression, activity and function, including migration and reactive oxygen species generation. Altogether, these results have major implications for the resolution of inflammation and indicate that MAO-A may promote metastatic potential in lung cancer cells.
PMID: 30021838 [PubMed – as supplied by publisher]