Dataset Information

Anticancer Activity of Tubulosine through Suppression of Interleukin-6-Induced Janus Kinase 2/Signal Transducer and Activation of Transcription 3 Signaling.

ABSTRACT:

Purpose

The chemical structure of tubulosine has been known since the mid-1960s. However, little is known about its biological and pharmacological functions. The aim of this study was to investigate the novel functions of tubulosine in cancer treatment, specifically in breast cancer.

Methods

An Unpaired (Upd)-induced Drosophila cell line and interleukin (IL)-6-stimulated human breast cancer cell lines were used to investigate the biological and pharmacological activities of tubulosine in vitro. To investigate the activities of tubulosine, we performed molecular and cellular experiments such as Western blot and reverse transcription polymerase chain reaction analyses, immunoprecipitation and terminal deoxynucleotidyl transferase dUTP nick end labeling assays, and immunofluorescence staining using breast cancer cell lines.

Results

Tubulosine exhibited anticancer activity in IL-6-stimulated human breast cancer cells. Moreover, tubulosine reduced the tyrosine phosphorylation level and transcriptional activity of signal transducer and activator of transcription (STAT) protein at 92E in Upd-induced Drosophila cells. Additionally, tubulosine suppressed IL-6-induced Janus kinase 2 (JAK2)/STAT3 signaling, resulting in decreased viability and induction of apoptotic cell death in breast cancer cells. Interestingly, inhibition of IL-6-induced JAK2/STAT3 signaling by tubulosine was associated with the blocking of IL-6 receptor (IL-6R) and glycoprotein 130 (gp130) binding.

Conclusion

Tubulosine exhibits anticancer activity through functional inhibition of IL-6-induced JAK2/STAT3 signaling by targeting IL-6R?/gp130 binding in breast cancer cells. These findings suggest that tubulosine may hold promise for the treatment of inflammation-associated cancers, including breast cancer.

SUBMITTER: Kim BH

PROVIDER: S-EPMC6769386 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Publications

Anticancer Activity of Tubulosine through Suppression of Interleukin-6-Induced Janus Kinase 2/Signal Transducer and Activation of Transcription 3 Signaling.

Kim Byung-Hak BH Yi Eun Hee EH Li Yu-Chen YC Park In-Chul IC Park Jung Youl JY Ye Sang-Kyu SK

Journal of breast cancer 20190901 3

<h4>Purpose</h4>The chemical structure of tubulosine has been known since the mid-1960s. However, little is known about its biological and pharmacological functions. The aim of this study was to investigate the novel functions of tubulosine in cancer treatment, specifically in breast cancer.<h4>Methods</h4>An Unpaired (Upd)-induced Drosophila cell line and interleukin (IL)-6-stimulated human breast cancer cell lines were used to investigate the biological and pharmacological activities of tubulo ...[more]

PMID: 31598337

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Project description:BACKGROUND Rheumatoid arthritis is an autoimmune disease that causes chronic joint inflammation and there is no cure. Baicalin, as an ingredient in the roots of Scutellaria baicalensis, is supposed to possess an anti-inflammatory effect. However, the protective effect of baicalin on collagen-induced arthritis requires further investigation. MATERIAL AND METHODS A model of rheumatoid arthritis was established in 20 mice (8- to 10-weeks old). The mice were randomly divided into 2 groups after modeling and then injected with saline or baicalin, respectively. The synovial fluids and tissues were collected, and the pressure pain threshold and clinical arthritis score were measured. The levels of tumor necrosis factor (TNF)-?, interlukin-1? (IL-1?), IL-6, matrix metalloproteinases (MMP)-2, MMP-9, nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and their downstream inflammatory mediators Janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3), extracellular signal-regulated kinases 1/2 (ERK1/2), p38, Jun N-terminal kinases (JNK) activation were detected using enzyme-linked immunosorbent assay (ELISA), and western blotting analyses. The mononuclear cells apoptosis ratio was calculated by flowcytometry analyses. RESULTS Baicalin significantly reduced disease activities in a rheumatoid arthritis mouse model, which were reflected by pressure pain thresholds and clinical arthritis scores. Relevant proinflammatory cytokines such as TNF-?, IL-1?, IL-6, gelatinases (MMP-2, MMP-9) and inducible enzymes (iNOS, COX-2) were generally suppressed. Moreover, baicalin treatment induced cells apoptosis in synovial fluid monocytes and markedly down regulated JAK1/STAT3 but not mitogen-activated protein kinases (MAPKs) expressions in synovium of arthritis. CONCLUSIONS These observations confirm the relief of rheumatoid arthritis by baicalin. Our results indicate the effect is related with the modulation of decreased proinflammatory cytokines and inflammatory markers. And the apoptosis promotion of monocytes in synovial fluid were also inhibited. Moreover, the molecular mechanism implies suppressed JAK1/STAT3 signaling with baicalin treatment.

Project description:OBJECTIVE:Glomerular mesangial expansion and podocyte loss are important early features of diabetic nephropathy, whereas tubulointerstitial injury and fibrosis are critical for progression of diabetic nephropathy to kidney failure. Therefore, we analyzed the expression of genes in glomeruli and tubulointerstitium in kidney biopsies from diabetic nephropathy patients to identify pathways that may be activated in humans but not in murine models of diabetic nephropathy that fail to progress to glomerulosclerosis, tubulointerstitial fibrosis, and kidney failure. RESEARCH DESIGN AND METHODS:Kidney biopsies were obtained from 74 patients (control subjects, early and progressive type 2 diabetic nephropathy). Glomerular and tubulointerstitial mRNAs were microarrayed, followed by bioinformatics analyses. Gene expression changes were confirmed by real-time RT-PCR and immunohistological staining. Samples from db/db C57BLKS and streptozotocin-induced DBA/2J mice, commonly studied murine models of diabetic nephropathy, were analyzed. RESULTS:In human glomeruli and tubulointerstitial samples, the Janus kinase (Jak)-signal transducer and activator of transcription (Stat) pathway was highly and significantly regulated. Jak-1, -2, and -3 as well as Stat-1 and -3 were expressed at higher levels in patients with diabetic nephropathy than in control subjects. The estimated glomerular filtration rate significantly correlated with tubulointerstitial Jak-1, -2, and -3 and Stat-1 expression (R(2) = 0.30-0.44). Immunohistochemistry found strong Jak-2 staining in glomerular and tubulointerstitial compartments in diabetic nephropathy compared with control subjects. In contrast, there was little or no increase in expression of Jak/Stat genes in the db/db C57BLKS or diabetic DBA/2J mice. CONCLUSIONS:These data suggest a direct relationship between tubulointerstitial Jak/Stat expression and progression of kidney failure in patients with type 2 diabetic nephropathy and distinguish progressive human diabetic nephropathy from nonprogressive murine diabetic nephropathy.

Dataset Information

Anticancer Activity of Tubulosine through Suppression of Interleukin-6-Induced Janus Kinase 2/Signal Transducer and Activation of Transcription 3 Signaling.

Purpose

Methods

Results

Conclusion

Publications

Anticancer Activity of Tubulosine through Suppression of Interleukin-6-Induced Janus Kinase 2/Signal Transducer and Activation of Transcription 3 Signaling.

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