In oxygen-deprived tumor cells ERp57 provides radioprotection and ensures proliferation via c-Myc, PLK1 and the AKT pathway

Ocklenburg, Tobias; Neumann, Fabian; Wolf, Alexandra; Vogel, James A.; Göpelt, Kirsten; Baumann, M.; Baumann, J; Kranz, Philip; Metzen, Eric; Brockmeier, Ulf

doi:10.1038/s41598-021-86658-5

Cited by 9 publications

(7 citation statements)

References 47 publications

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“…Nuclear VDR is a type of nuclear hormone receptor, and most of the biological actions are mediated through the VDR-mediated control of target genes [ 47 ]. Pdia3 is a pleiotropic, ER-resident protein that has been detected on the cell surface [ 48 ], in the cytoplasm [ 49 ], and in mitochondria [ 50 ]. Pdia3 is located in cellular compartments other than the ER and is involved in a variety of cellular functions such as signal transduction, protein trafficking, interacting with mTOR, and regulation of STAT3 signaling [ 51 , 52 ].…”

Section: Discussionmentioning

confidence: 99%

Long-Term Vitamin D Deficiency Results in the Inhibition of Cell Proliferation and Alteration of Multiple Gastric Epithelial Cell Lineages in Mice

Sirajudeen

Shah

Ayoub

et al. 2022

IJMS

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Over one billion people globally are vitamin D (VD) deficient. Studies on the biological roles of VD are numerous but very little on the stomach. This project aims to understand how gastric homeostasis is affected by VD deficiency caused by prolonged exposure to darkness alone or combined with VD deficient diet. Three groups of C57/BL6 mice were subjected to different light exposure conditions and diets for 12 months (n = 8–12/group): control—12 h/12 h light/dark SDL (Standard Diet/Light), 24 h dark SDD (Standard Diet/Dark), and 24 h dark VDD (VD deficient diet/Dark). Stomach samples were collected for different multi-label lectin-/immuno-histochemical and qRT-PCR analyses, and the serum for LC-MS-MS. We found that the membrane VD receptor is expressed widely in the stomach when compared to nuclear VD receptors. Compared to SDL, VDD mice developed mucous cell expansion with increased mucins-mRNA (3.27 ± 2.73 (p < 0.05)) increased apoptotic cells, 15 ± 7 (p ≤ 0.001)); decreased cell proliferation, 4 ± 4 (p < 0.05)) and decreased acid secretion 33 ± 2 μEq/kg (p ≤ 0.0001)). Interestingly, mice exposed to full darkness developed mild VD deficiency with higher VD epimer levels: 11.9 ± 2.08 ng/mL (p ≤ 0.0001)), expansion in zymogenic cell number (16 ± 3 (p ≤ 0.01)), and a reduction in acid secretion (18 ± 2 μEq/kg (p ≤ 0.0001)). In conclusion, changes in light exposure or VD levels have serious physiological effects on the gastric mucosa, which should be considered during the management of gastric disorders.

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Section: Discussionmentioning

confidence: 99%

Long-Term Vitamin D Deficiency Results in the Inhibition of Cell Proliferation and Alteration of Multiple Gastric Epithelial Cell Lineages in Mice

Sirajudeen

Shah

Ayoub

et al. 2022

IJMS

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“…PLK1 is known to play an important role in initiating, completing, and maintaining the cell mitotic cycle 25 . Elevated levels of PLK1 transcription, or protein expression, have been found in a variety of human solid tumors, including lung, breast, stomach, cervical, and colon cancers 26 . Multiple studies have shown that PLK1/ERK is a key pathway to induce malignant transformation and tumor formation of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Tanshinone IIA suppresses the progression of lung adenocarcinoma through regulating CCNA2-CDK2 complex and AURKA/PLK1 pathway

Zhang

Zhou

et al. 2021

Sci Rep

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Lung adenocarcinoma (LUAD) belongs to a subgroup of non-small cell lung cancer (NSCLC) with an increasing incidence all over the world. Tanshinone IIA (TSA), an active compound of Salvia miltiorrhiza Bunge., has been found to have anti-tumor effects on many tumors, but its anti-LUAD effect and its mechanism have not been reported yet. In this study, bio-information analysis was applied to characterize the potential mechanism of TSA on LUA, biological experiments were used to verify the mechanisms involved. TCGA, Pubchem, SwissTargetPrediction, Venny2.1.0, STRING, DAVID, Cytoscape 3.7.2, Omicshare, GEPIA, RSCBPDB, Chem Draw, AutoDockTools, and PyMOL were utilized for analysis in the bio-information analysis and network pharmacology. Our experiments in vitro focused on the anti-LUAD effects and mechanisms of TSA on LUAD cells (A549 and NCI-H1975 cells) via MTT, plate cloning, Annexin V-FITC and PI dual staining, flow cytometry, and western blot assays. A total of 64 differentially expressed genes (DEGs) of TSA for treatment of LUAD were screened out. Gene ontology and pathway analysis revealed characteristic of the DEGs network. After GEPIA-based DEGs confirmation, 46 genes were considered having significant differences. Further, 10 key DEGs (BTK, HSD11B1, ADAM33, TNNC1, THRA, CCNA2, AURKA, MIF, PLK1, and SORD) were identified as the most likely relevant genes from overall survival analysis. Molecular Docking results showed that CCNA2, CDK2 and PLK1 had the lowest docking energy. MTT and plate cloning assays results showed that TSA inhibited the proliferation of LUAD cells in a concentration-dependent manner. Annexin V-FITC and PI dual staining and flow cytometry assays results told that TSA promoted the apoptosis of the two LUAD cells in different degrees, and induced cycle arrest in the G1/S phase. Western blot results showed that TSA significantly down-regulated the expression of CCNA2, CDK2, AURKA, PLK1, and p-ERK. In summary, TSA could suppress the progression of LUAD by inducing cell apoptosis and arresting cell cycle, and these were done by regulating CCNA2-CDK2 complex and AURKA/PLK1 pathway. These findings are the first to demonstrate the molecular mechanism of TSA in treatment of LUAD combination of network bio-information analysis and biological experiments in vitro.

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“…Following the KEGG signal pathway analysis, the mechanisms of CP in the treatment of HUA mainly involved inflammation and apoptosis signaling pathways, including PI3K/Akt, TNF, FoxO, MAPK, HIF-1, TLR, NLRP3, AMPK, and NF-κB. The PI3K/Akt pathway is a crucial pathway that regulates cell proliferation, cell survival, cell cycle progression, and cancer metabolism (Ocklenburg et al, 2021). Studies have found that in the Uox-knock-out-induced HUA and nephropathy rat line, the PI3K inhibitor 3-MA alleviates kidney injury accompanied by renal fibrosis, macrophage infiltration, and expression of NLRP3 and IL-1β in injured kidneys (Wu et al, 2021).…”

Section: Figurementioning

confidence: 99%

Integrating network pharmacology and experimental validation to clarify the anti-hyperuricemia mechanism of cortex phellodendri in mice

Cheng

et al. 2022

Front. Pharmacol.

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Hyperuricemia (HUA), a common metabolic disease, is treated as the second-largest metabolic disease after diabetes in China. Cortex Phellodendri (CP) is one of the most frequently used herbal medicines for treating gout or HUA. However, the mechanism underlying the anti-HUA effect of CP is still unrevealed. Hence, this study aimed to explore the pharmacological mechanism of CP against HUA using network pharmacology coupled with in vivo experimental validation. Active compounds and potential targets of CP, as well as the potential targets related to HUA, were retrieved from multiple open-source databases. The drug-disease overlapping targets were obtained by Venn diagram analysis and used to construct the herb-component-target (HCT), protein-protein-interaction (PPI), and component-target-pathway (CTP) networks. The functional enrichment analysis was also performed for further study. Furthermore, a HUA mouse model was induced by a combination of intraperitoneal injection of potassium oxonate (PO, 300 mg/kg) and intragastric administration of hypoxanthine (HX, 300 mg/kg) daily for 10 days. Different dosages of CP (200, 400, and 800 mg/kg) were orally given to mice 1 h after modeling. The results showed that 12 bioactive compounds and 122 drug-disease overlapping targets were obtained by matching 415 CP-related targets and 679 HUA-related targets, and berberine was one of the most important compounds with the highest degree value. The core targets of CP for treating HUA were TP53, MAPK8, MAPK3, IL-6, c-Jun, AKT1, xanthine oxidase (XOD), and ATP-binding cassette subfamily G member 2 (ABCG2). The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment results showed that the anti-HUA effect of CP mainly involved the pathways of inflammation and apoptosis, such as PI3K/Akt, TNF, MAPK, TLR, AMPK, NF-κB, and NLRP3 signaling pathways. In vivo animal experiment further confirmed the hypouricemic effect of CP in a HUA mouse model, as evidenced by significantly restored kidney histological deteriorations, and considerably decreased levels of serum uric acid (sUA), creatinine (Cre), blood urea nitrogen (BUN), and hepatic UA. Furthermore, the hypouricemic action of CP in vivo might be attributed to its suppression of XOD activity in the liver, rather than ABCG2 in the kidney. Real-time qPCR (RT-qPCR) and Western blot analysis also confirmed the key roles of the hub genes in CP against HUA. In conclusion, CP exhibited therapeutic effect against HUA via multi-compounds, multi-targets, and multi-pathways. It possessed anti-HUA and nephroprotective effects via suppressing XOD activity, and reversed the progression of renal injury by exerting anti-inflammatory and anti-apoptotic effects.

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In oxygen-deprived tumor cells ERp57 provides radioprotection and ensures proliferation via c-Myc, PLK1 and the AKT pathway

Cited by 9 publications

References 47 publications

Long-Term Vitamin D Deficiency Results in the Inhibition of Cell Proliferation and Alteration of Multiple Gastric Epithelial Cell Lineages in Mice

Long-Term Vitamin D Deficiency Results in the Inhibition of Cell Proliferation and Alteration of Multiple Gastric Epithelial Cell Lineages in Mice

Tanshinone IIA suppresses the progression of lung adenocarcinoma through regulating CCNA2-CDK2 complex and AURKA/PLK1 pathway

Integrating network pharmacology and experimental validation to clarify the anti-hyperuricemia mechanism of cortex phellodendri in mice

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