MAPK14 (p38α) inhibition effects against metastatic gastric cancer cells: A potential biomarker and pharmacological target

Mesquita, Felipe Pantoja; Moreira-Nunes, Caroline Aquino; Silva, Emerson Lucena da; Lima, Luína Benevides; Daniel, Julio Paulino; Zuerker, William J.; Brayner, Mirna; Moraes, Maria Elisabete Amaral de; Montenegro, Raquel Carvalho

doi:10.1016/j.tiv.2020.104839

Cited by 30 publications

(15 citation statements)

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“…AKT1 is a key regulator of PI3K/AKT signaling and participates in cell proliferation and apoptosis [43]. MAPK14 and MAPK1 are important members of the mitogen-activated protein kinase family, and MAPK14 is an important biomarker of metastatic gastric cancer, where its inhibition signi cantly reduces the progression of advanced gastric cancer [44]. Additionally, MAPK1 affects the progression of breast and ovarian cancers by participating in multiple signaling pathways [45,46], and AKT1 is closely related to cancer and a variety of diseases through its roles in metabolic regulation and multiple signaling pathways [47,48].…”

Section: Discussionmentioning

confidence: 99%

Analysis and verification of the molecular mechanism of Evodia in the treatment of nasopharyngeal carcinoma using network pharmacology and molecular docking

Yang

et al. 2022

Preprint

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Background: Nasopharyngeal carcinoma (NPC) is a neoplasm of the head and neck, with the highest incidence and mortality rates occurring in East and Southeast Asia. Evodia rutaecarpa is a tree that is native to Korea and China, and its fruit (hereafter referred to as Evodia) exhibits remarkable antitumor properties. However, little is known about its mechanism of action in NPC. In this study, we employed network pharmacology to identify targets of the active Evodia compounds in nasopharyngeal carcinoma and generate an interaction network.Methods: The active ingredients of Evodia and the targets for nasopharyngeal carcinoma were obtained from multiple databases, and an interaction network was constructed via the Cytoscape and STRING databases. The key biological processes and signaling pathways were predicted using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Molecular docking technology was used to identify the affinity and activity of target genes, while The Cancer Genome Atlas and Human Protein Atlas databases were used to analyze differential expression. Cell Counting Kit (CCK)-8 and Annexin V-FITC/PI dual fluorescence staining were used for experimental verification.Results: Active Evodia compounds included quercetin, isorhamnetin, and evodiamine, and important nasopharyngeal carcinoma targets included MAPK14, AKT1, RELA, MAPK1, JUN, and p53, whose content in the lipid and atherosclerosis signaling pathways was also high. Additionally, we verified the high affinity and activity of the active compounds through molecular docking, and the target proteins were verified using immunohistochemistry and differential expression analyses. Furthermore, Cell Counting Kit-8 assays and Annexin V-FITC/propidium iodide dual-fluorescence staining verified that isorhamnetin inhibited the proliferation of nasopharyngeal carcinoma cells and induced apoptosis, respectively.Conclusion: These results elucidated the molecular mechanism of Evodia and demonstrated its ability to alter the proliferation and apoptosis of nasopharyngeal carcinoma cells through multiple targets and pathways, thereby providing evidence for its clinical application.

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Section: Discussionmentioning

confidence: 99%

Analysis and verification of the molecular mechanism of Evodia in the treatment of nasopharyngeal carcinoma using network pharmacology and molecular docking

Yang

et al. 2022

Preprint

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“…Until recently, clinical evaluation of a family of key regulators, the p38MAPK isoforms have widely focused on the study and consideration of p38α as a biomarker of cancer [ 71 ]. However, recent evaluations of p38 implicate the additional isoforms with cancer cell biology.…”

Section: Discussionmentioning

confidence: 99%

p38β - MAPK11 and its role in female cancers

et al. 2021

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Background The p38MAPK family of Mitogen Activated Protein Kinases are a group of signalling molecules involved in cell growth, survival, proliferation and differentiation. The widely studied p38α isoform is ubiquitously expressed and is implicated in a number of cancer pathologies, as are p38γ and p38δ. However, the mechanistic role of the isoform, p38β, remains fairly elusive. Recent studies suggest a possible role of p38β in both breast and endometrial cancer with research suggesting involvement in bone metastasis and cancer cell survival. Female tissue specific cancers such as breast, endometrial, uterine and ovary account for over 3,000,000 cancer related incidents annually; advancements in therapeutics and treatment however require a deeper understanding of the molecular aetiology associated with these diseases. This study provides an overview of the MAPK signalling molecule p38β (MAPK11) in female cancers using an in-silico approach. Methods A detailed gene expression and methylation analysis was performed using datasets from cBioportal, CanSar and MEXPRESS. Breast, Uterine Endometrial, Cervical, Ovarian and Uterine Carcinosarcoma TCGA cancer datasets were used and analysed. Results Data using cBioportal and CanSAR suggest that expression of p38β is lower in cancers: BRCA, UCEC, UCS, CESC and OV compared to normal tissue. Methylation data from SMART and MEXPRESS indicate significant probe level variation of CpG island methylation status of the gene MAPK11. Analysis of the genes’ two CpG islands shows that the gene was hypermethylated in the CpG1 with increased methylation seen in BRCA, CESC and UCEC cancer data sets with a slight increase of expression recorded in cancer samples. CpG2 exhibited hypomethylation with no significant difference between samples and high levels of expression. Further analysis from MEXPRESS revealed no significance between probe methylation and altered levels of expression. In addition, no difference in the expression of BRCA oestrogen/progesterone/HER2 status was seen. Conclusion This data provides an overview of the expression of p38β in female tissue specific cancers, showing a decrease in expression of the gene in BRCA, UCEC, CESC, UCS and OV, increasing the understanding of p38β MAPK expression and offering insight for future in-vitro investigation and therapeutic application.

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“…5) as follows: MAPK1, also known as ERK2, is associated with tumor proliferation 42 , differentiation, and invasion, and its upregulation is associated with the occurrence and development of various tumors 43 .Mitogen-activated protein kinase 3(MAPK3),knows as ERK1,whereas ERK pathway mediates cellular survival and growth， as well as leads to increased apoptosis 44 ， the study suggests that MAPK3 has close relationship with cardiomyocyte apoptosis in IRI 45 . MAPK14 gene, known as p38α, is one of the four family members of MAP kinase which exert versatile functions in diverse cellular processes in cancer: cell cycle regulation, proliferation, survival and motility 46 ,as well as MAPK14 (P38) can be involved in a variety of cellular stresses, including internal metabolic stress, DNA damage, external growth factor pathway, cell-matrix interaction and intercellular communication 47,48 .Mesquita et al have showed p38α inhibition Cellular migration was impaired and decreased the gastric cancer cell proliferation by provoking cell cycle arrest and cell death 49 .In this study ,the phosphorylation site T180/Y182 was downregulated by merecidin .Ephrin type-B receptor 2(EPHB2) is associated with the occurrence and development of A variety of diseases.EPHB2 has been shown to be associated with cells apoptosis in many studies 50,51 . 52 Dong et al have suggested that EphB/ephrinB reverse signaling is involved in retinal ganglion cell (RGC) apoptosis in experimental glaucoma.In our study ,the phosphorylation site S776/S575of EphB2 Upregulated.…”

Section: Discussionmentioning

confidence: 99%

Phospho-Proteomic Analysis of The Effect of Merecidin Inhibiting the Human Lung Adenocarcinoma A549 Cells

Wang

Jia

Zhang

et al. 2021

Preprint

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Objectives: Merecidin induced A549 cells apoptosis. The present study aimed to assess the differentially phosphorylated proteins in lung cancer A549 cells treated with antibacterial peptide merecidin. Methods: TMT/iTRAQ labeling, LC-MS/MS analysis, HPLC grading, IMAC modification and enrichment, and liquid chromatography-mass spectrometry of peptide. The data of proteins were filtered according to the localization probability >0.75 standard. The phosphorylated proteomics data were analyzed using GO, KEGG, and STRING databases. Western blots examined the changes in phosphorylated protein expression. Results: Protein function enrichment showed significant changes in the phosphorylation level with respect to protein binding, metabolic activity, molecular function regulation, cell process, and biological function regulation. Integrated pathway bioinformatics results showed that differential proteins are associated with several pathways, including mTOR and AMPK etc. Screening of the COG database revealed differentiated phosphorylated proteins in cell signal transduction, RNA transcription, translation processing and modification, ribosome synthesis of proteins, cytoskeleton protein formation, intracellular material transport, secretion, and vesicle transport. Protein interaction level analysis identified an interaction network with HDAC1, RPL23A, SRSF3H, and NCBP1.etc. The phosphorylated proteomics data and showed that after merecidin treatment, ATG2B and ULK1s were significantly upregulated, while MAPK1 and AKT were significantly downregulated. In addition, Western blot also showed the upregulated level of ATG13,ULK1;MAPK1 downregulated. Conclusion: The results verified the feasibility of phosphorylated proteomics analysis, confirmed the signaling pathways, and suggested that merecidin may induce autophagy of lung adenocarcinoma A549 cells.

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MAPK14 (p38α) inhibition effects against metastatic gastric cancer cells: A potential biomarker and pharmacological target

Cited by 30 publications

References 50 publications

Analysis and verification of the molecular mechanism of Evodia in the treatment of nasopharyngeal carcinoma using network pharmacology and molecular docking

Analysis and verification of the molecular mechanism of Evodia in the treatment of nasopharyngeal carcinoma using network pharmacology and molecular docking

p38β - MAPK11 and its role in female cancers

Phospho-Proteomic Analysis of The Effect of Merecidin Inhibiting the Human Lung Adenocarcinoma A549 Cells

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