MAPK (mitogen-activated protein kinase) signaling pathways regulate a variety of biological processes through multiple cellular mechanisms. In most of these processes, such as apoptosis, MAPKs have a dual role since they can act as activators or inhibitors, depending on the cell type and the stimulus. In this review, we present the main pro- and anti-apoptotic mechanisms regulated by MAPKs, as well as the crosstalk observed between some MAPKs. We also describe the basic signaling properties of MAPKs (ultrasensitivity, hysteresis, digital response), and the presence of different positive feedback loops in apoptosis. We provide a simple guide to predict MAPKs’ behavior, based on the intensity and duration of the stimulus. Finally, we consider the role of MAPKs in osmostress-induced apoptosis by using Xenopus oocytes as a cell model. As we will see, apoptosis is plagued with multiple positive feedback loops. We hope this review will help to understand how MAPK signaling pathways engage irreversible cellular decisions.

Hyperosmotic shock induces cytochrome c release and capase-3 activation in Xenopus oocytes, but the regulators and signaling pathways involved are not well characterized. Here we show that hyperosmotic shock induces rapid calpain activation and high levels of Smac/DIABLO release from the mitochondria before significant amounts of cytochrome c are released to promote caspase-3 activation. Calpain inhibitors or EGTA microinjection delays osmostress-induced apoptosis, and blockage of Smac/DIABLO with antibodies markedly reduces cytochrome c release and caspase-3 activation. Hyperosmotic shock also activates the p38 and JNK signaling pathways very quickly. Simultaneous inhibition of both p38 and JNK pathways reduces osmostress-induced apoptosis, while sustained activation of these kinases accelerates the release of cytochrome c and caspase-3 activation. Therefore, at least four different pathways early induced by osmostress converge on the mitochondria to trigger apoptosis. Deciphering the mechanisms of hyperosmotic shock-induced apoptosis gives insight for potential treatments of human diseases that are caused by perturbations in fluid osmolarity.

BackgroundUlcerative colitis (UC) is an inflammatory disease of the intestinal mucosa, and its incidence is steadily increasing worldwide. Intestinal immune dysfunction has been identified as a central event in UC pathogenesis. However, the underlying mechanisms that regulate dysfunctional immune cells and inflammatory phenotype remain to be fully elucidated.MethodsTranscriptome profiling of intestinal mucosa biopsies were downloaded from the GEO database. Robust Rank Aggregation (RRA) analysis was performed to identify statistically changed genes and differentially expressed genes (DEGs). Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to explore potential biological mechanisms. CIBERSORT was used to evaluate the proportion of 22 immune cells in biopsies. Weighted co-expression network analysis (WGCNA) was used to determine key module-related clinical traits. Protein-Protein Interaction (PPI) network and Cytoscape were performed to explore protein interaction network and screen hub genes. We used a validation cohort and colitis mouse model to validate hub genes. Several online websites were used to predict competing endogenous RNA (ceRNA) network.ResultsRRA integrated analysis revealed 1838 statistically changed genes from four training cohorts (adj. p-value < 0.05). GSEA showed that statistically changed genes were enriched in the innate immune system. CIBERSORT analysis uncovered an increase in activated dendritic cells (DCs) and M1 macrophages. The red module of WGCNA was considered the most critical module related to active UC. Based on the results of the PPI network and Cytoscape analyses, we identified six critical genes and transcription factor NF-κB. RT-PCR revealed that andrographolide (AGP) significantly inhibited the expression of hub genes. Finally, we identified XIST and three miRNAs (miR-9-5p, miR-129-5p, and miR-340-5p) as therapeutic targets.ConclusionsOur integrated analysis identified four hub genes (CXCL1, IL1B, MMP1, and MMP10) regulated by NF-κB. We further revealed that AGP decreased the expression of hub genes by inhibiting NF-κB activation. Lastly, we predicted the involvement of ceRNA network in the regulation of NF-κB expression. Collectively, our results provide valuable information in understanding the molecular mechanisms of active UC. Furthermore, we predict the use of AGP and small RNA combination for the treatment of UC.

In the last few years, cellular metabolic reprogramming has been acknowledged as a hallmark of human cancer and evaluated for its crucial role in supporting the proliferation and survival of human cancer cells. In a variety of human tumours, including hepatocellular carcinoma (HCC), breast cancer and non-small-cell lung cancer (NSCLC), a large amount of carbon is reused in serine/glycine biosynthesis, accompanied by higher expression of the key glycine synthetic enzyme mitochondrial serine hydroxymethyltransferase 2 (SHMT2). This enzyme can convert serine into glycine and a tetrahydrofolate-bound one-carbon unit, ultimately supporting thymidine synthesis and purine synthesis and promoting tumour growth. In tumour samples, elevated expression of SHMT2 was found to be associated with poor prognosis. In this review, the pivotal roles of SHMT2 in human carcinogenesis are described, highlighting the underlying regulatory mechanisms through promotion of tumour progression. In conclusion, SHMT2 may serve as a prognostic marker and a target for anticancer therapies.

Lysyl oxidase-like 2 (LOXL2) is a member of the scavenger-receptor cysteine-rich (SRCR) repeat carrying LOX family. Although LOXL2 is suspected to be involved in histone association and chromatin modification, the role of LOXL2 in epigenetic regulation during tumorigenesis and cancer progression remains unclear. Here, we report that nuclear LOXL2 associates with histone H3 and catalyzes H3K36ac deacetylation and deacetylimination. Both the N-terminal SRCR repeats and the C-terminal catalytic domain of LOXL2 carry redundant deacetylase catalytic activity. Overexpression of LOXL2 markedly reduced H3K36 acetylation and blocked H3K36ac-dependent transcription of genes, including c-MYC, CCND1, HIF1A, and CD44. Consequently, LOXL2 overexpression reduced cancer cell proliferation in vitro and inhibited xenograft tumor growth in vivo. In contrast, LOXL2 deficiency resulted in increased H3K36 acetylation and aberrant expression of H3K36ac-dependent genes involved in multiple oncogenic signaling pathways. Female LOXL2 deficient mice spontaneously developed uterine hypertrophy and uterine carcinoma. Moreover, silencing LOXL2 in cancer cells enhanced tumor progression and reduced the efficacy of cisplatin and anti-programmed cell death 1 (PD-1) combination therapy. Clinically, low nuclear LOXL2 expression and high H3K36ac levels corresponded to poor prognosis in uterine endometrial carcinoma patients. These results suggest that nuclear LOXL2 restricts cancer development in the female reproductive system via regulation of H3K36ac deacetylation.