Targeting the JAK2/STAT3 Pathway—Can We Compare It to the Two Faces of the God Janus?

Jaśkiewicz, Anna; Domoradzki, Tomasz; Pająk, Beata

doi:10.3390/ijms21218261

Cited by 32 publications

(17 citation statements)

References 106 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found that the Y705 and S727 sites of Stat3 were phosphorylated upon Zinc treatment, suggesting that zinc activates Stat3. Previous studies reported that the upstream kinases of S727‐Stat3 were mainly MAPKs, such as ERK, JNK, or P38 (Bode et al, 2012; Ryu et al, 2018; Wang et al, 2019), and the upstream kinase of Y705‐Stat3 was JAK2 (Ceyzériat et al, 2016; Jaśkiewicz et al, 2020). Our experiment showed that activation of ERK and JAK2 regulated the phosphorylation of S727 and Y705 of Stat3, respectively, in zinc‐activated astrocytes.…”

Section: Discussionmentioning

confidence: 99%

Zinc induces reactive astrogliosis through ERK‐dependent activation of Stat3 and promotes synaptic degeneration

Zhang

Yang

Wang

et al. 2021

Journal of Neurochemistry

View full text Add to dashboard Cite

Reactive astrogliosis is an early event in Alzheimer's disease (AD) brain and plays a key role in synaptic degeneration in AD development. Zinc accumulates in extracellular fraction and synaptosomes in AD human brains with its effect on reactive astrocytes remaining unknown. Through Western blotting, Quantitative polymerase chain reaction (qPCR), and immunofluorescence detection on primary astrocytes treated by zinc and/or zinc chelator, we revealed that zinc induced harmful A1‐type reactive astrogliosis in cultured primary astrocytes; the latter, promoted synaptic degeneration in primary neurons. The mechanism investigation showed that zinc induced activation of extracellular regulated protein kinase (ERK) and Janus kinase 2 (JAK2), which phosphorylated signal transduction and transcription activator 3 (Stat3) at serine 727 (S727‐Stat3) and tyrosine 705 (Y705‐Stat3), respectively, resulting in activation of Stat3. Stat3 phosphorylation at S727 by ERK plays a key role in zinc‐induced astrogliosis. These data imply a new molecular mechanism of reactive astrogliosis in AD, in which excessive zinc activates Stat3 through up‐regulating ERK signaling pathway.

show abstract

Section: Discussionmentioning

confidence: 99%

Zinc induces reactive astrogliosis through ERK‐dependent activation of Stat3 and promotes synaptic degeneration

Zhang

Yang

Wang

et al. 2021

Journal of Neurochemistry

View full text Add to dashboard Cite

show abstract

“…JAK2 serves as a signaling hub that integrates extracellular signals from interleukin receptors and oncogenic receptor tyrosine kinases into STAT3, which phosphorylates STAT3 at Y705 and homodimerizes with p-STAT3 to induce its nuclear translocation and transcriptional activity through interaction with its phosphorylated Y705 site and SH2 domain ( 53 , 54 ). STAT3 binds to the promoters of its target genes to induce tumor cell migration, growth, and differentiation and plays an important role in the development of a variety of tumors ( 55 ).…”

Section: Discussionmentioning

confidence: 99%

Network Pharmacology Study and Experimental Validation of Yiqi Huayu Decoction Inducing Ferroptosis in Gastric Cancer

Song

Fang

et al. 2022

Front. Oncol.

View full text Add to dashboard Cite

ObjectiveThis study aimed to identify the mechanism of Yiqi Huayu Decoction (YQHY) induced ferroptosis in gastric cancer (GC) by using network pharmacology and experimental validation.MethodsThe targets of YQHY, ferroptosis-related targets, and targets related to GC were derived from databases. Following the protein–protein interaction (PPI) network, the hub targets for YQHY induced ferroptosis in GC were identified. Furthermore, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were used to analyze the hub targets from a macro perspective. We verified the hub targets by molecular docking, GEPIA, HPA, and the cBioPortal database. Finally, we performed cell viability assays, quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, lipid peroxidation, and GSH assays to explore the mechanism of YQHY induced ferroptosis in GC.ResultsWe identified the main active compounds and hub targets: Quercetin, DIBP, DBP, Mipax, Phaseol and TP53, ATM, SMAD4, PTGS2, and ACSL4. KEGG enrichment analyses indicated that the JAK2-STAT3 signaling pathway may be a significant pathway. Molecular docking results showed that the main active compounds had a good binding activity with the hub targets. The experimental results proved that YQHY could induce ferroptosis in AGS by increasing the MDA content and reducing the GSH content. qRT–PCR and Western blot results showed that YQHY can induce ferroptosis in GC by affecting the JAK2-STAT3 pathway and the expression of ACSL4.ConclusionsThis study indicated that YQHY can induce ferroptosis in GC by affecting the JAK2–STAT3 pathway and the expression of ACSL4, and induction of ferroptosis may be one of the possible mechanisms of YQHY’s anti-recurrence and metastasis of GC.

show abstract

“…JAK2/STAT3 pathway is a signal transducer and activator in tumorigenesis and development. 29 The anti‐cancer function of GL63 in HCC was also achieved by inactivating the JAK2/STAT3 pathway. 7 However, it remains unclear about the regulatory mechanism of GL63 in the JAK2/STAT3 signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

A curcumin analog GL63 inhibits the malignant behaviors of hepatocellular carcinoma by inactivating the JAK2/STAT3 signaling pathway via the circular RNA zinc finger protein 83/microRNA‐324‐5p/cyclin‐dependent kinase 16 axis

Zhao

Nie

Dong

et al. 2021

J of Gastro and Hepatol

View full text Add to dashboard Cite

Background and Aim: (1E,4E)-1,5-bis(2-bromophenyl) penta-1,4-dien-3-one (GL63) is a curcumin analog that can protect against carcinogenesis in hepatocellular carcinoma (HCC). The aim of this study was to explore the molecular mechanism of GL63 in HCC. Methods: Cell viability was examined by cell counting kit-8 (CCK-8) assay. Circular RNA zinc finger protein 83 (circZNF83), microRNA-324-5p (miR-324-5p), and cyclin-dependent kinase 16 (CDK16) levels were measured via the quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation was assessed using colony formation assay. Flow cytometry was performed for detecting cell cycle and apoptosis. Protein analysis was conducted by western blot. Cell migration and invasion were determined using transwell assay. Target relation was analyzed using dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. The function of GL63 in vivo was researched by xenograft model in mice. Results: GL63 inhibited the circZNF83 expression in HCC cells. CircZNF83 overexpression attenuated the inhibitory effects of GL63 on HCC cell growth, cell cycle progression, migration, and invasion but the promoting effect on cell apoptosis. CircZNF83 served as a sponge of miR-324-5p and circZNF83/miR-324-5p axis was involved in the functional regulation of GL63 in HCC progression. Moreover, CDK16 was a downstream target of miR-324-5p and circZNF83 could regulate the CDK16 expression by sponging miR-324-5p. The anti-tumor function of GL63 was also related to the miR-324-5p/CDK16 axis. In addition, GL63 inactivated the JAK2/STAT3 pathway via downregulating circZNF83 to mediate the miR-324-5p/CDK16 axis. GL63 also repressed tumor growth in vivo through the circZNF83/miR-324-5p/CDK16-mediated JAK2/STAT3 signal inhibition. Conclusion:This study suggested GL63 impeded the HCC development by blocking the JAK2/STAT3 signaling pathway via mediating the circZNF83/miR-324-5p/CDK16 axis.

show abstract

Targeting the JAK2/STAT3 Pathway—Can We Compare It to the Two Faces of the God Janus?

Cited by 32 publications

References 106 publications

Zinc induces reactive astrogliosis through ERK‐dependent activation of Stat3 and promotes synaptic degeneration

Zinc induces reactive astrogliosis through ERK‐dependent activation of Stat3 and promotes synaptic degeneration

Network Pharmacology Study and Experimental Validation of Yiqi Huayu Decoction Inducing Ferroptosis in Gastric Cancer

A curcumin analog GL63 inhibits the malignant behaviors of hepatocellular carcinoma by inactivating the JAK2/STAT3 signaling pathway via the circular RNA zinc finger protein 83/microRNA‐324‐5p/cyclin‐dependent kinase 16 axis

Contact Info

Product

Resources

About