Background
Glutamyl-prolyl-tRNA synthetase (EPRS/GluRS) is primarily part of the multi-synthetase complex that may play a key role in cancer development. However, the biological function, molecular ...mechanism, and inhibitor of EPRS have not been investigated in gastric cancer (GC).
Methods
Immunohistochemistry was performed to detect the expression of EPRS in human gastric tumor tissues. Knocking down of EPRS, cell-derived xenograft mouse model, and patient-derived xenograft mouse model was used to identify the biological function of EPRS. Immunoprecipitation was applied to elucidate the interaction between EPRS and SCYL2. Computer docking model and multiple in vitro and in vivo experiments were conducted to discover EPRS inhibitors.
Results
Here, we report that EPRS is frequently overexpressed in GC tissues compared to that adjacent controls and its overexpression predicts poor prognosis in GC patients. Functionally, high expression of EPRS positively co-relates with GC development both in vitro and in vivo. Mechanistically, EPRS directly binds with SCYL2 to enhance the activation of WNT/GSK-3β/β-catenin signaling pathway and the accumulation of β-catenin in the nuclear, leading to GC cell proliferation and tumor growth. Moreover, we identified that xanthoangelol (XA) and 4-hydroxyderricin (4-HD) can directly bind to EPRS to block WNT/GSK-3β/β-catenin signaling pathway. More importantly, XA and 4-HD restrain gastric cancer patient-derived xenograft tumor growth and
Helicobacter pylori
combined with alcohol-induced atrophic gastritis and gastric tumorigenesis.
Conclusion
These findings unveil a promising strategy for GC prevention and therapy by targeting EPRS-mediated WNT/GSK-3β/β-catenin cascades. Moreover, XA and 4-HD may be effective reagents used for GC prevention and therapy.
This review, with 290 references, presents the fascinating area of iodinated natural products over the past hundred years for the first time. It covers literature published from 1896 to 2014 and ...refers to compounds isolated from both biogenic and abiotic sources. In total, 182 naturally-occurring organoiodine compounds are recorded. The emphasis is on the compounds together with the relevant biological activities, sources, collection places, countries of origin, biosynthetic studies, and first total syntheses.
This review, with 290 references, presents the fascinating area of iodinated natural products over the past hundred years for the first time.
Fibroblast growth factor receptor (FGFR) 2 and its downstream signaling cascades, PI3 K/AKT/mTOR is playing an important role in cell survival and proliferations. In this study, we firstly found that ...picrasidine Q (PQ), an alkaloid component extracted from Angelica keiskei species, has the capacity of anti‐cell transformation and anti‐cancer. After ligand shape similarity approach of PQ, we found that PQ targeted FGFR 2 and verified by FGFR2 kinase assay as well as computational docking model. FGFR2 highly expressed in esophageal cancer tissues and PQ inhibited fibroblast growth factor (FGF)‐induced cell transformation. Furthermore, PQ inhibited cell proliferation and induced cell cycle arrest and apoptosis in KYSE30, KYSE410, and KYSE450 esophageal squamous cell carcinoma (ESCC) cells. It was confirmed by detecting of biological markers such as cyclinD1, cyclinD3 and cyclinB1 for cell cycle or cleaved caspase‐7, caspase‐3, and PARP for apoptosis. PQ targeting of FGFR2 kinase activities suppressed downstream target proteins including phosphorylation of AKT and mTOR but not MEK/ERK signaling pathways. Taken together, our results are the first to identify that PQ might be a chemopreventive and chemotherapeutic agent by direct targeting FGFR2 and inhibiting cell proliferation of ESCC cells.
FGFR2 is highly expressed in ESCC patients. FGFR2 is a direct target of Picrasidine Q. Picrasidine Q inhibits cell growth of ESCC cells. Picrasidine Q suppresses down‐stream signaling pathways of FGFR2.
Eupafolin is the main bioactive component extracted from the traditional Chinese medicine Ay Tsao (
Artemisia vulgaris
L.), and its anti-tumor activity has had been studied in previous researches. ...T-LAK cell-originated protein kinase (TOPK) belongs to serine/threonine protein kinase and is highly expressed in several cancer cells and tissues, such as colon cancer, lung cancer, esophagus cancer, and so on. Therefore, it was recognized as an important target for treating tumors. Nowadays, we found that eupafolin suppressed TOPK activities at the first time
in vitro
and
in vivo
. The cells study indicated that eupafolin suppressed TOPK activities in JB6 Cl41 and KYSE450 cells. Furthermore, knockdown of TOPK in KYSE450 cells decreased their sensitivities to eupafolin. The animal study showed that the injection of eupafolin in patient-derived xenograft (PDX) mouse effectively suppressed tumor growth. Histone H3 and Ki67 were reduced, and cleaved caspase 3 was increased in tumor tissues after eupafolin treatment. To sum up, eupafolin as an TOPK inhibitor can suppress growth of esophagus cancer
in vitro
and
in vivo
. The TOPK downstream signaling molecule histone H3 in tumor tissues was also reduced after eupafolin treatment. In short, eupafolin can suppress growth of esophagus cancer cells as an TOPK inhibitor both
in vitro
and
in vivo
.
Four new prenylxanthones, emerixanthones A-D (1-4), together with six known analogues (5-10), were isolated from the culture of the deep-sea sediment derived fungus Emericella sp. SCSIO 05240, which ...was identified on the basis of morphology and ITS sequence analysis. The newstructures were determined by NMR (1H, 13C NMR, HSQC, HMBC, and 1H-1H COSY), MS, CD, and optical rotation analysis. The absolute configuration of prenylxanthone skeleton was also confirmed by the X-ray crystallographic analysis. Compounds 1and 3 showed weak antibacterial activities, and 4 displayed mild antifungal activities against agricultural pathogens.
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