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1.
Biomed Pharmacother ; 105: 848-855, 2018 Sep.
Article in English | MEDLINE | ID: mdl-30021377

ABSTRACT

Despite significant progress in the treatment of breast cancer due to advances in surgery, cytotoxic agents, and endocrine therapy, the prognosis for patients has not improved much. Accumulated evidence indicates that heterogeneous nuclear ribonucleoprotein M (hnRNPM) and Wnt/ß-catenin function as tumor oncogenes in the progression of many cancers. The present study aimed to explore whether HnRNPM/ß-catenin signaling molecules might serve as a genetic target for breast cancer treatment. To shed light on this issue, quantitative real-time polymerase chain reaction (qRT-PCR) detection, Western blotting, and immunohistochemical staining were performed. The hnRNPM is expressed at a much higher level in breast cancer tissues and cell lines than in noncancerous tissues and cell lines. In vitro studies revealed that overexpressed hnRNPM promoted cell proliferation and colony formation but inhibited cell apoptosis. In vivo results demonstrated that upregulation of hnRNPM dramatically increased breast cancer xenograft tumor growth. Western blotting and immunofluorescence studies revealed that hnRNPM markedly activated the Wnt/ß-catenin pathway and catalyzed its translocation from the cytoplasm to the nucleus by targeting axin, a negative regulator of Wnt/ß-catenin signaling in MCF-7 and KPL-4 cells. Elevated levels of c-Myc and cyclin D1 were observed when MCF-7 and KPL-4 cells were transfected with a hnRNPM vector. These findings indicate that the hnRNPM/axin/ß-catenin signaling pathway acts as an oncogenic promoter in the progression of breast cancer, suggesting that hnRNPM may be a potential target for the treatment of this disease.


Subject(s)
Axin Protein/physiology , Breast Neoplasms/metabolism , Disease Progression , Heterogeneous-Nuclear Ribonucleoprotein Group M/biosynthesis , Signal Transduction/physiology , beta Catenin/physiology , Animals , Biomarkers, Tumor/biosynthesis , Breast Neoplasms/pathology , Female , Humans , MCF-7 Cells , Mice , Mice, Inbred C57BL , Mice, SCID , Xenograft Model Antitumor Assays/methods
2.
Oncol Lett ; 11(6): 4040-4044, 2016 Jun.
Article in English | MEDLINE | ID: mdl-27313737

ABSTRACT

The aim of the present study was to investigate the association between the expression levels of transforming growth factor-ß1 (TGF-ß1) and the clinical pathological characteristics and prognosis of triple negative breast cancer (TNBC) through study of TNBC patient tissue samples. The biological effects of TGF-ß1 on TNBC cells and the potential signal transduction pathway are additoinally investigated. Immunohistochemistry was utilized to investigate expression changes of the positive rate of TGF-ß1 in the TNBC, compared with the non-TNBC group, to explain the association between TGF-ß1 and clinical pathological characteristics and prognosis. MDA-MB-231 cells were treated with TGF-ß1 and subsequently the invasion and migration abilities, and the expression of proteins in certain signaling pathways were assessed before and after the treatment. Positive expression of TGF-ß1 was observed in 52.5% of TNBC tissue samples, which was higher than that observed in non-TNBC group (27.5%). High levels of TGF-ß1 expression were not significantly associated age, menopausal status, family history of cancer or tumor size; however, tumor histological grade and axillary lymph node metastasis were significantly associated (P<0.05). In addition, when the TGF-ß1 expression levels are higher, the 5-year disease-free survival rate is lower. TGF-ß1 expression promoted the invasion and migration of MDA-MB-231 cells, and the expression of Smad2 protein and P38 protein was increased, indicating that Smad2 protein and the P38 signaling pathway may serve an important role in TNBC.

3.
Eur J Pharmacol ; 713(1-3): 78-88, 2013 Aug 05.
Article in English | MEDLINE | ID: mdl-23665494

ABSTRACT

Male hypogonadism is frequently accompanied with type 2 diabetes due to testicular dysfunction, but the origin of the pathogenesis is not known. We measured whether pro-inflammatory factors including endoplasmic reticulum (ER) stress chaperones and inhibitory κBß (IκBß) contribute to testis damage in type 2 diabetic rats produced by a high-fat diet (HFD) and low dose streptozotocin (STZ). We determined whether these can be attenuated by the anti-inflammatory activity of argirein a derivative of rhein as compared to valsartan. Reduced testosterone and LH (luteinizing hormone) levels in serum were significant in association with a decrease in the levels of mRNA and steroidogenic acute regulatory protein (StAR), insulin receptor substrate (IRS-1), activated IκBß and ER stress chaperone C/EBP homologous protein (CHOP) in the diabetic testis and sperm count, motility and sexual behaviors were reduced in vivo. Additionally, Leydig cells cultured with high glucose showed upregulated IκBß, ER stress sensor PERK (PKR-like ER kinase) and p-Akt/Akt in vitro. These changes may be due to a component of inflammation linked to activated NADPH oxidase and were significantly alleviated by either argirein or valsartan. In conclusion, diabetic testopathy induced by a HFD and low STZ is characterized by an entity of inflammation and is alleviated by argirein and valsartan through normalizing activated IκBß and ER stress.


Subject(s)
Anthraquinones/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Arginine/therapeutic use , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Type 2/complications , Endoplasmic Reticulum Stress/drug effects , Hypogonadism/prevention & control , I-kappa B Proteins/metabolism , Tetrazoles/therapeutic use , Valine/analogs & derivatives , Animals , Anthraquinones/administration & dosage , Anti-Inflammatory Agents/administration & dosage , Arginine/administration & dosage , Diabetes Mellitus, Experimental/immunology , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 2/immunology , Diabetes Mellitus, Type 2/metabolism , Diet, High-Fat/adverse effects , Drug Combinations , Hypogonadism/etiology , Hypogonadism/immunology , Hypogonadism/metabolism , Male , Rats , Rats, Sprague-Dawley , Sexual Behavior, Animal/drug effects , Streptozocin/pharmacology , Tetrazoles/administration & dosage , Valine/administration & dosage , Valine/therapeutic use , Valsartan
4.
J Pharm Pharmacol ; 64(8): 1138-45, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22775217

ABSTRACT

OBJECTIVES: We investigated the effect of argirein on acute inflammation edema and examined that aquaporin 4 (AQP4), p66Shc and activating transcription factor (ATF-6) might be involved in carrageenan-induced rat paw inflammation and be reversed by argirein, rhein and indometacin, but not L-arginine. METHODS: Inflammation was produced by carrageenan injected into rat paw and treated orally with argirein (100 mg/kg), rhein (100 mg/kg), L-arginine (100 mg/kg) or indometacin (5 mg/kg). Inflammatory oedema and biomarkers were examined. KEY FINDINGS: Swelling was reduced by argirein, rhein and indometacin; argirein was more effective than rhein at 1 h following medication. Activation of AQP4, p66Shc, ATF-6, NADPH oxidase subunits p22phox, gp91phox and matrix metalloproteinase 2 (P < 0.01) was significant and was suppressed by arginine, rhein and indometacin but not by l-arginine. CONCLUSIONS: Activated AQP4, endoplasmic reticulum stress and p66Shc were actively implicated in the inflammation and these were suppressed by argirein, and its activity is favorable due to synergism in combination with L-arginine.


Subject(s)
Anthraquinones/therapeutic use , Aquaporin 4/metabolism , Arginine/therapeutic use , Endoplasmic Reticulum Stress/drug effects , Indomethacin/therapeutic use , Inflammation/drug therapy , Shc Signaling Adaptor Proteins/metabolism , Activating Transcription Factor 6/metabolism , Animals , Anthraquinones/pharmacology , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Arginine/pharmacology , Biomarkers/metabolism , Carrageenan , Drug Combinations , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Edema/drug therapy , Female , Indomethacin/pharmacology , Inflammation/chemically induced , Inflammation/metabolism , Male , Matrix Metalloproteinase 2/metabolism , NADPH Oxidases/metabolism , Rats , Rats, Sprague-Dawley , Src Homology 2 Domain-Containing, Transforming Protein 1
5.
Inflammation ; 35(3): 1031-40, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22095404

ABSTRACT

We investigated the anti-inflammatory activities of argirein and rhein on inflammatory edema in rat paw which was caused by complete adjuvant, compared with ibuprofen. We hypothesized that the adjuvant-induced inflammation is attributed to upregulation of activating transcript factor 6 (ATF6; a chaperone for endoplasmic reticulum (ER) stress), p66Shc (an adaptive protein modulating oxidative stress), and NADPH oxidase subunits p22phox and gp91phox in the inflamed tissues. Biomarkers were measured in the rat paw in association with monitoring swellings. The primary inflammatory edema of the injected paw occurred rapidly and sustained over a couple of days, and the secondary inflammation developed 2 weeks later. The inflammatory edema was accompanied by upregulation of cytokines including ATF6, p66Shc, p22phox, gp91phox, and MMP-2 and an increase in ratio of p-Akt/Akt in the afflicted paw. These were suppressed by either argirein and rhein or ibuprofen. These findings indicate that ER stress, upregulated p66Shc, and phosphorylated Akt are actively implicated in the inflammatory zone caused by adjuvant injection. These biomarkers were causal factors responsible for inflammation of the afflicted paw and were suppressed by a supermolecule argirein and rhein, and the anti-inflammatory activities of the two compounds were comparable to that of ibuprofen.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Endoplasmic Reticulum Stress , Inflammation/pathology , Proto-Oncogene Proteins c-akt/metabolism , Shc Signaling Adaptor Proteins/metabolism , Activating Transcription Factor 6/metabolism , Adjuvants, Immunologic , Animals , Anthraquinones/pharmacology , Anti-Inflammatory Agents/therapeutic use , Arthritis, Rheumatoid/chemically induced , Arthritis, Rheumatoid/drug therapy , Edema/chemically induced , Edema/drug therapy , Edema/pathology , Female , Ibuprofen/pharmacology , Inflammation/chemically induced , Inflammation/drug therapy , Inflammation/metabolism , Male , Matrix Metalloproteinase 2/metabolism , Membrane Glycoproteins/metabolism , NADPH Oxidase 2 , NADPH Oxidases/metabolism , Rats , Rats, Sprague-Dawley , Src Homology 2 Domain-Containing, Transforming Protein 1
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