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 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 γ (PPARγ) and that signal transducer and activator of transcription 6 (STAT6) plays a crucial role in facilitating the transcriptional activity of PPARγ. We further report that the IL-13-STAT6-15-LO-PPARγ 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.

No abstract

No abstract

Monoamine oxidase-A (MAO-A), a pro-oxidative enzyme catalyzes the oxidative deamination of endogenous and exogenous monoamines/neurotransmitters like dopamine, serotonin, norepinephrine or tyramine and converting them into their corresponding aldehydes and reactive oxygen species (ROS). Hyperactivity of MAO-A has been shown to be involved in depression, neuro-degeneration including Parkinson’s and Alzheimer’s diseases, neuropsychiatric disorders and cardiovascular diseases. Our recent results however demonstrated the involvement of MAO-A in promoting aggressiveness of lung carcinoma. We found both constitutive and inducible expression of MAO-A in non-small cell lung cancer cells H1299 and in A549 lung epithelial carcinoma cells. By using knockout (by CRISPR-Cas9 gene editing technology) or knockdown (using MAO-A specific esiRNA) MAO-A cells we demonstrated the role of MAO-A in promoting lung cancer aggressiveness and epithelial to mesenchymal transition (EMT). From our observations, we can conclude that MAO-A may be considered as a potential therapeutic target for the intervention and treatment of lung carcinoma.

Parkinson disease (PD) is linked to alpha-synuclein (aS) aggregation and deposition of amyloid in the substantia nigra region of the brain tissues. Recent reports suggested that oligomeric assembly structure could be neurotoxic to neuronal cells. In the current investigation we produced two distinct classes of aS oligomers and link the protein conformation state and stability to neuronal cell toxicity. Natural oligomers (NO) enriched with alpha-helical folds are produced in storage of aS at below -20°C for 7 days. Induced oligomer (IO), often observed in the aggregation pathway of aS were made incubating the protein solution at 37 °C. Natural oligomers remained stable and did not transform into beta-sheet rich amyloid fiber and exhibited higher toxicity (80% cell death) compared to induced oligomers. Natural oligomers were ovular shape and the size ranged between 4-5.5 nm. It maintained significant number (~ 60%) of residues in alpha-helical conformational space. However, initiation of hydrophobic zipping with beta sheet conformation was evidenced in induced oligomer (IO) and a lesser number residues (45%) remained with preference to alpha-helical secondary structure. Hydrophobic collapse leads the transformation of IO into thermodynamically most stable beta-sheet rich amyloid fibril. Molten globule like secondary structure stabilized by H-bonding in natural oligomers caused enhanced stability and cellular toxicity compared to induced oligomer. Thus off-pathway/natural oligomers could be plausible reason of neuronal cell death and possible cause of Parkinson disease.

Methotrexate is a well-known antineoplastic drug used to prevent cancer aggravation. Despite being a targeted therapeutic approach, its administration comes with the risk of cancer recurrence, plausibly through its proven off-target effect on focal adhesions. Since FA dynamics is dependent on force transmission through its constituent proteins, including talin, methotrexate might affect the mechanical activity of these proteins. Here we have combined single-molecule studies, computational dynamics, cell-based assays, and genomic analysis to unveil the focal adhesion-regulating role of methotrexate central to its effect on talin dynamics and downstream pathways. Interestingly, our single-molecule force spectroscopic study shows that methotrexate modulates the bimodal force distribution of talin in a concentration-dependent manner. Steered molecular dynamics reveal that methotrexate-talin interactions alter talin mechanical stability exposing their vinculin binding sites. Finally, we found that methotrexate-regulated talin-dynamics remodel cancer cell mechanical phenotypes like cell polarity, adhesion, and migration by regulating talin-vinculin association-mediated YAP signaling. These results further correlate with genomic analysis of methotrexate-treated patients, demonstrating its clinical importance. Taken together, these findings disseminate the effects of methotrexate-modulated mechanosensitivity of adhesion proteins on cellular events.

Monoamine oxidase A (MAO-A) is a flavoenzyme that catalyzes biogenic amines into the corresponding aldehydes by oxidative deamination. Although MAO-A is primarily associated with depression and antisocial behaviour, dysregulation of MAO-A has been associated with neurodegenerative diseases and cardiovascular disorders. Moreover, the contribution of MAO-A in the resolution of inflammation is well established. Recent reports reveal the unanticipated role of MAO-A in tumorigenesis. In this review we provide informations that MAO-A is involved in the progression and metastasis of many different cancer cells including prostate cancer, colorectal cancer, hepatocellular carcinoma and lung cancer. We further discuss the regulatory mechanisms that control tumorigenesis, progression and metastasis in these different type of cancer cells. Altogether these informations indicate that MAO-A can be a general therapeutic target in cancer treatment.