Desensitization of the Growth Hormone-Induced Janus Kinase 2 (Jak 2)/Signal Transducer and Activator of Transcription 5 (Stat5)-Signaling Pathway Requires Protein Synthesis and Phospholipase C*

The molecular mechanisms that promote progression of localized prostate cancer to hormone-refractory and disseminated disease are poorly understood. Prolactin (Prl) is a local growth factor produced in high-grade prostate cancer, and exogenously added Prl in tissue or explant cultures of normal and malignant prostate is a strong mitogen and survival factor for prostate epithelium. The key signaling proteins that mediate the biological effects of Prl in prostate cancer are Signal Transducer and Activator of Transcription (Stat)-5a/5b via activation of Janus kinase-2. Importantly, inhibition of Stat5a/b in prostate cancer cells induces apoptotic death. Using a specific Prl receptor antagonist (Δ1–9G129R-hPRL), we demonstrate here for the first time that autocrine Prl in androgen-independent human prostate cancer cells promotes cell viability via Stat5 signaling pathway. Furthermore, we examined a unique clinical material of human hormone refractory prostate cancers and metastases and show that autocrine Prl is expressed in 54% of hormone-refractory clinical human prostate cancers and 62% prostate cancer metastases. Finally, we demonstrate that autocrine Prl is expressed from both the proximal and distal promoters of the Prl gene in clinical human prostate cancers and in vivo and in vitro human prostate cancer models, independently of pituitary transcription factor-1 (Pit-1). Collectively, the data provide novel evidence for the concept that autocrine Prl signaling pathway is involved in growth of hormone-refractory and metastatic prostate cancer. The study also provides support for the use of Prl receptor antagonists or other therapeutic strategies to block the Prl-Janus kinase-2-Stat5 signaling pathway in advanced prostate cancer.

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Inadequacy of the Janus Kinase 2/Signal Transducer and Activator of Transcription Signal Transduction Pathway to Mediate Episodic Growth Hormone-Dependent Regulation of Hepatic CYP2C11

Molecular Pharmacology ◽

10.1124/mol.104.005454 ◽

2004 ◽

Vol 67 (3) ◽

pp. 891-901 ◽

Cited By ~ 22

Author(s):

Ashish S. Verma ◽

Ravindra N. Dhir ◽

Bernard H. Shapiro

Keyword(s):

Signal Transduction ◽

Growth Hormone ◽

Signal Transduction Pathway ◽

Janus Kinase ◽

Signal Transducer ◽

Transduction Pathway ◽

Janus Kinase 2 ◽

Episodic Growth

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Erythropoietin Attenuates Experimental Contrast-Induced Nephrology: A Role for the Janus Kinase 2/Signal Transducer and Activator of Transcription 3 Signaling Pathway

Frontiers in Medicine ◽

10.3389/fmed.2021.634882 ◽

2021 ◽

Vol 8 ◽

Author(s):

Jia Yang ◽

Jiaojiao Zhou ◽

Xin Wang ◽

Ling Ji ◽

Siwen Wang ◽

...

Keyword(s):

Signaling Pathway ◽

Janus Kinase ◽

Cell Counting ◽

Signal Transducer ◽

Janus Kinase 2 ◽

Protein Levels ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway ◽

Transcription 3

The aim of the present study was to investigate the effect of erythropoietin (EPO) on contrast-induced nephrology (CIN) in vivo and in vitro. Male C57BL/6J mice were divided into four groups: control, CIN (iohexol 6.0 g/kg), EPO (3,000 IU/kg), and CIN+EPO. Hematoxylin and eosin (H&E) staining and biochemical index analyses were performed to evaluate renal injury. The cellular proliferation rate was detected using the Cell Counting Kit-8 (CCK-8) assay. In addition, a terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and flow cytometric assay were used to assess the apoptosis of tissue and cells, respectively. Renal protein expression associated with apoptosis, pyroptosis, and signaling pathways was determined by Western blot (WB) assays for tissues and cells. The results showed that EPO significantly decreased serum creatinine, blood urea nitrogen, and cystatin C levels and alleviated renal histological changes in vivo. The protein levels of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway components were overexpressed in the EPO treatment group. Furthermore, EPO suppressed the cell apoptosis and pyroptosis; decreased the protein levels of cleaved caspase-3, Bax, gasdermin D (GSDMD), and caspase-1; and enhanced the expression of Bcl-2. In summary, EPO could exert renoprotective effect by activating the JAK2/STAT3 signaling pathway, which may be a novel potential therapy for the treatment of CIN in the clinic.

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Chrysophanol attenuated isoproterenol‐induced cardiac hypertrophy by inhibiting Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway

Cell Biology International ◽

10.1002/cbin.11146 ◽

2019 ◽

Vol 43 (6) ◽

pp. 695-705 ◽

Cited By ~ 4

Author(s):

Jing Yuan ◽

Huiqi Hong ◽

Yuhong Zhang ◽

Jing Lu ◽

Youhui Yu ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Signaling Pathway ◽

Janus Kinase ◽

Signal Transducer ◽

Janus Kinase 2 ◽

Transcription 3

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As4S4 Exhibits Good Killing Effect on Multiple Myeloma Cells Via Repressing SOCS1 Methylation-Mediated JAK2/STAT3 Signaling Pathway

Technology in Cancer Research & Treatment ◽

10.1177/1533033819896806 ◽

2019 ◽

Vol 18 ◽

pp. 153303381989680

Author(s):

Di Wu ◽

Wei Dong ◽

Kun Fang ◽

Mengchang Wang

Keyword(s):

Multiple Myeloma ◽

Cell Viability ◽

Signaling Pathway ◽

Plasma Cells ◽

Janus Kinase ◽

Cytokine Signaling ◽

Signal Transducer ◽

Janus Kinase 2 ◽

Suppressor Of Cytokine Signaling ◽

Transcription 3

Objective: This study aimed to investigate the effect of tetra-arsenic tetra-sulfide on treating multiple myeloma and its potential regulation on suppressor of cytokine signaling 1 methylation-mediated Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway. Methods: Tetra-arsenic tetra-sulfide with different concentrations were used to treat U266 cells, and cell viability was measured at 12, 24, and 48 hours with 0 μM tetra-arsenic tetra-sulfide treatment as control by Cell Counting Kit-8 assay. Suppressor of cytokine signaling 1 methylation and expression were determined by methylation-specific polymerase chain reaction, quantitative polymerase chain reaction, and Western blot, respectively, in U266 cells and normal plasma cells and in U266 cells treated by tetra-arsenic tetra-sulfide. Then, rescue experiments were performed by transfecting suppressor of cytokine signaling 1 small interfering RNA into tetra-arsenic tetra-sulfide-treated U266 cells. Besides, phosphor–Janus kinase 2, Janus kinase 2, phospho–signal transducer and activator of transcription 3, and signal transducer and activator of transcription 3 expressions were determined by Western blot. Results: Tetra-arsenic tetra-sulfide inhibited U266 cell viability efficiently in a dose- and time-dependent manner. Suppressor of cytokine signaling 1 methylation was higher while suppressor of cytokine signaling 1 expression was lower in U266 cells compared to normal plasma cells; when treated by tetra-arsenic tetra-sulfide, suppressor of cytokine signaling 1 methylation was decreased while suppressor of cytokine signaling 1 expression was increased in U266 cells, along with the reduced phospho–Janus kinase 2 and phospho–signal transducer and activator of transcription 3 expressions. Then, suppressor of cytokine signaling 1 small interfering RNA enhanced the cell viability and phospho–Janus kinase 2 as well as phospho–signal transducer and activator of transcription 3 expressions in both tetra-arsenic tetra-sulfide treatment-free and tetra-arsenic tetra-sulfide-treated U266 cells. Conclusion: Tetra-arsenic tetra-sulfide exhibits good killing effect on multiple myeloma cells via repressing suppressor of cytokine signaling 1 methylation and downstream Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway, which might serve as a potential treatment option for multiple myeloma.

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