Increased expression of plasminogen activator inhibitor type-1 (PAI-1) in HEPG2 cells induced by insulin mediated by the 3′-untranslated region of the PAI-1 gene and its pharmacologic implications

Miyagawa, Ryu; Asakura, Takefumi; Nakamura, Tomomi; Okada, Hiromi; Iwaki, Soichiro; Sobel, Burton E.; Fujii, Satoshi

doi:10.1097/mca.0b013e328335790e

Cited by 11 publications

(3 citation statements)

References 30 publications

(29 reference statements)

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“…Growth of MDA-MB-231 cells in low serum (0.1%) medium supplemented with insulin, transferrin and selenium inhibited CDCP1 cleavage (Figure 5b), likely because of the combined effect of decreased (serum-derived) plasminogen and insulin-induced upregulation of PAI-1 expression. 31,32 Previous studies have implicated CDCP1 cleavage in increased tyrosine phosphorylation of cCDCP1, coincident with increased signaling functions. 25,26 Together the results in Figures 5a and b indicate that the components of cell culture media including serum levels, supplementation with glucocorticoids such as dexamethasone and hydrocortisone, supplementation with insulin, as well as factors produced by the cancer cells themselves, such as TGFβ, and the plasminogen activators uPA and tPA have important roles in controlling CDCP1 cleavage, and consequently its tyrosine phosphorylation and biological activity.…”

Section: Resultsmentioning

confidence: 99%

Glucocorticoids and histone deacetylase inhibitors cooperate to block the invasiveness of basal-like breast cancer cells through novel mechanisms

et al. 2012

Oncogene

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Aggressive cancers often express E-cadherin in cytoplasmic vesicles rather than on the plasma membrane and this may contribute to the invasive phenotype of these tumors. Therapeutic strategies are not currently available that restore the anti-invasive function of E-cadherin in cancers. MDA-MB-231 cells are a frequently used model of invasive triple-negative breast cancer, and these cells express low levels of E-cadherin that is mislocalized to cytoplasmic vesicles. MDA-MB-231 cell lines stably expressing wild-type E-cadherin or E-cadherin fused to glutathione S-transferase or green fluorescent protein were used as experimental systems to probe the mechanisms responsible for cytoplasmic E-cadherin localization in invasive cancers. Although E-cadherin expression partly reduced cell invasion in vitro, E-cadherin was largely localized to the cytoplasm and did not block the invasiveness of the corresponding orthotopic xenograft tumors. Further studies indicated that the glucocorticoid dexamethasone and the highly potent class I histone deacetylase (HDAC) inhibitor largazole cooperated to induce E-cadherin localization to the plasma membrane in triple-negative breast cancers, and to suppress cellular invasion in vitro. Dexamethasone blocked the production of the cleaved form of the CDCP1 (that is, CUB domain-containing protein 1) protein (cCDCP1) previously implicated in the pro-invasive activities of CDCP1 by upregulating the serine protease inhibitor plasminogen activator inhibitor-1. E-cadherin preferentially associated with cCDCP1 compared with the full-length form. In contrast, largazole did not influence CDCP1 cleavage, but increased the association of E-cadherin with γ-catenin. This effect on E-cadherin/γ-catenin complexes was shared with the nonisoform selective HDAC inhibitors trichostatin A (TSA) and vorinostat (suberoylanilide hydroxamic acid, SAHA), although largazole upregulated endogenous E-cadherin levels more strongly than TSA. These results demonstrate that glucocorticoids and HDAC inhibitors, both of which are currently in clinical use, cooperate to suppress the invasiveness of breast cancer cells through novel, complementary mechanisms that converge on E-cadherin.

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Section: Resultsmentioning

confidence: 99%

Glucocorticoids and histone deacetylase inhibitors cooperate to block the invasiveness of basal-like breast cancer cells through novel mechanisms

et al. 2012

Oncogene

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“…The subsequent hyperglycemia can lead to ROS generation and oxidative stress [77], which can trigger systemic inflammation and mediate further FFA production [9]. This process ultimately leads to a prothrombotic tendency by enhancing coagulation while inhibiting fibrinolysis [78,79], which in some cases can contribute to the pathogenesis of VTE associated with abdominal obesity [32]. Indeed, insulin resistance has been reported to increase the risk of VTE in a BMI-dependent manner [80].…”

Section: In Relation To Inflammation and Insulin Resistancementioning

confidence: 99%

The effects of obesity on venous thromboembolism: A review

Yang¹,

Staercke²,

Hooper³

2012

OJPM

132

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Obesity has emerged as a global health issue that is associated with wide spectrum of disorders, including coronary artery disease, diabetes mellitus, hypertension, stroke, and venous thromboembolism (VTE). VTE is one of the most common vascular disorders in the United States and Europe and is associated with significant mortality. Although the association between obesity and VTE appears to be moderate, obesity can interact with other environmental or genetic factors and pose a significantly greater risk of VTE among individuals who are obese and who are exposed simultaneously to several other risk factors for VTE. Therefore, identification of potential interactions between obesity and certain VTE risk factors might offer some critical points for VTE interventions and thus minimize VTE morbidity and mortality among patients who are obese. However, current obesity measurements have limitations and can introduce contradictory results in the outcome of obesity. To overcome these limitations, this review proposes several future directions and suggests some avenues for prevention of VTE associated with obesity as well.

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“…HepG2 cells were seeded into 96-well plates in RPMI-1640 supplemented with 10% FBS and penicillin (100 U/mL)/streptomycin (100 μg/mL), cultured in a humidified incubator (5% CO 2 ) at 37 1C for 24 h. The insulin-resistant cell model was induced according to the previous reference method (Miyagawa et al, 2010). In brief, HepG2 cells were incubated with a fresh medium containing 1% FBS and 1 Â 10 À 6 mol/L bovine insulin for 24 h. Cells were treated with 10 À 9 mol/L insulin and fresh or dried POL extract (0.25, 0.5, and 1.0 mg/mL, respectively) or metformin (0.086 mg/mL) in RPMI-1640 medium containing 1% FBS.…”

Section: Glucose Consumptionmentioning

confidence: 99%

Comparison on hypoglycemic and antioxidant activities of the fresh and dried Portulaca oleracea L. in insulin-resistant HepG2 cells and streptozotocin-induced C57BL/6J diabetic mice

Zheng

Yuan

et al. 2015

Journal of Ethnopharmacology

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Increased expression of plasminogen activator inhibitor type-1 (PAI-1) in HEPG2 cells induced by insulin mediated by the 3′-untranslated region of the PAI-1 gene and its pharmacologic implications

Cited by 11 publications

References 30 publications

Glucocorticoids and histone deacetylase inhibitors cooperate to block the invasiveness of basal-like breast cancer cells through novel mechanisms

Glucocorticoids and histone deacetylase inhibitors cooperate to block the invasiveness of basal-like breast cancer cells through novel mechanisms

The effects of obesity on venous thromboembolism: A review

Comparison on hypoglycemic and antioxidant activities of the fresh and dried Portulaca oleracea L. in insulin-resistant HepG2 cells and streptozotocin-induced C57BL/6J diabetic mice

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