SB-431542

Background: Macrophages constitute the main part of infiltrating immune cells in Malignant pleural mesothelioma (MPM) and abnormally high ratios of M2 macrophages are present in both pleural effusion and tissue samples of MPM patients. Whether MPM cells affect formation of M2 macrophages is poorly understood. In this study, we focused on identification of MPM-cells-derived soluble factors with M2-promoting effects. Methods: Media of malignant pleural mesothelioma cells were collected and soluble factors affecting macrophages were analyzed by mass spectrometry. TGF-β receptor inhibitor SB431542 was used as the entry point to explore the downstream mechanism of action by qRT-PCR, WB and immunofluorescence. Results: The serum-free culture media collected from the human MPM cells Meso1 and Meso2 significantly enhanced expression of the M2 signature molecules including IL-10, TGF-β and CD206 in the human macrophages THP-1, while the culture medium of the human MPM cells H2452 did not show such M2-promoting effects. Analysis of proteins by mass spectrometry and ELISA suggested that Leucine rich α2 glycoprotein 1(LRG1) was a potential candidate. LRG1 time- and dose-dependently increased expression of the M2 signature molecules, confirming its M2-promoting effects. Furthermore, LRG1's M2-promoting effects were reduced by the TGF-β receptor inhibitor SB431542, and LRG1 increased phosphorylation of Smad2, indicating that M2-promoting effects of LRG1 were via the TGF-β receptor/Smad2 signaling pathway. Conclusions: Our results provide a potential M2-promoting new member, LRG1, which contributes to the immune escape of MPM via the TGF-β receptor/Smad2 signaling pathway.

Currently, researchers are exploring the conversion of astrocytes into functional mature neurons and gradually exploring the conversion of glioma into neurons. We report that SLCDS (SB431542, LDN193189, CHIR99021, DAPT, and SKL2001) has been shown to convert human glioma cells into mature neuron-like cells. The converted cells exhibited upregulation of DCX, TuJ1, MAP2, NeuN, and GAD67, while the expressions of EGFR, PDGFR, Ki67, and vimentin were inhibited. The nTFs, such as NeuroD1 and Sox2, were upregulated, along with TF genes associated with neurogenesis and tumor suppression. We have finally confirmed that overexpressing nTFs can induce the conversion of glioma cells into neuronal cells. This study demonstrates that SLCDS can activate the expression of nTFs in human glioma cells and induce the conversion of human glioma cells into neuron-like cells. Additionally, SLCDS inhibits the expressions of EGFR, PDGFR, Ki67, and Vimentin in gliomas. Our findings offer a potential approach for treating glioma.