Estrogen-Induced Retinal Endothelial Cell Proliferation: Possible Involvement of Pigment Epithelium-Derived Factor and Phosphoinositide 3-Kinase/Mitogen-Activated Protein Kinase Pathways

Signaling events involving angiotensin IV (ANG IV)-mediated pulmonary artery endothelial cell (PAEC) proliferation were examined. ANG IV significantly increased upstream phosphatidylinositide (PI) 3-kinase (PI3K), PI-dependent kinase-1 (PDK-1), extracellular signal-related kinases (ERK1/2), and protein kinase B-α/Akt (PKB-α) activities, as well as downstream p70 ribosomal S6 kinase (p70S6K) activities and/or phosphorylation of these proteins. ANG IV also significantly increased 5-bromo-2′-deoxy-uridine incorporation into newly synthesized DNA in a concentration- and time-dependent manner. Pretreatment of cells with wortmannin and LY-294002, inhibitors of PI3K, or rapamycin, an inhibitor of the mammalian target of rapamycin kinase and p70S6K, diminished the ANG IV-mediated activation of PDK-1 and PKB-α as well as phosphorylation of p70S6K. Although an inhibitor of mitogen-activated protein kinase kinase, PD-98059, but not rapamycin, blocked ANG IV-induced phosphorylation of ERK1/2, both PD-98059 and rapamycin independently caused partial reduction in ANG IV-mediated cell proliferation. However, simultaneous treatment with PD-98059 and rapamycin resulted in total inhibition of ANG IV-induced cell proliferation. These results demonstrate that ANG IV-induced DNA synthesis is regulated in a coordinated fashion involving multiple signaling modules in PAEC.

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Human Epididymis Protein 4 Inhibits Proliferation of Human Ovarian Cancer Cells Via the Mitogen-Activated Protein Kinase and Phosphoinositide 3-Kinase/AKT Pathways

International Journal of Gynecological Cancer ◽

10.1097/igc.0000000000000078 ◽

2014 ◽

Vol 24 (3) ◽

pp. 427-436 ◽

Cited By ~ 14

Author(s):

Xiuli Kong ◽

Xiaohong Chang ◽

Hongyan Cheng ◽

RuiQiong Ma ◽

Xue Ye ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Proliferation ◽

Protein Kinase ◽

Caspase 3 ◽

Mitogen Activated Protein Kinase ◽

Human Epididymis Protein 4 ◽

Human Epididymis ◽

Mitogen Activated Protein ◽

Associated Proteins ◽

Phosphoinositide 3 Kinase

ObjectivesHuman epididymis protein 4 (HE4) is a promising novel biomarker for the detection of epithelial ovarian cancer (EOC). The role of HE4 in EOC tumorigenesis is unclear. This study investigated the cellular and molecular mechanisms of HE4 in ovarian cancer cell proliferation.MethodsWe generated HE4-overexpressing SKOV3 cells and silenced HE4 gene expression in SKOV3.ip1 cells. We used the cell counting kit 8 assay to evaluate cell proliferation and Western blotting to analyze the expression of proliferation- and apoptosis-associated proteins such as Bax, Bcl-2, and caspase 3.ResultsOverexpression of HE4 in SKOV3, an ovarian carcinoma cell line, inhibited cell proliferation, In contrast, HE4 silencing in SKOV3.ip1 cells promoted cell proliferation; however, conditioned medium containing HE4 and human recombinant HE4 protein had no effect on proliferation in both SKOV3 and SKOV3.ip1 cells. Human epididymis protein 4 inhibited MEK, extracellular signal–regulating kinase 1/2, and AKT phosphorylation but promoted c-Jun N-terminal protein kinase 1/2/3 and c-JUN phosphorylation; however, p38 phosphorylation was impaired in HE4-overexpressing and silenced cells. Human epididymis protein 4 had no effect on epidermal growth factor receptor phosphorylation or on the apoptosis-associated proteins Bax, Bcl-2, and caspase 3.ConclusionsHuman epididymis protein 4 might play a protective role in the progression of EOC by inhibiting cell proliferation. Antiproliferative activity was mediated by intracellular HE4 and not the secreted protein. Human epididymis protein 4 might inhibit cell proliferation by regulating the mitogen-activated protein kinase and phosphoinositide 3-kinase/AKT signal transduction pathways in vitro.

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Visfatin inhibits apoptosis of pancreatic β-cell line, MIN6, via the mitogen-activated protein kinase/phosphoinositide 3-kinase pathway

Journal of Molecular Endocrinology ◽

10.1530/jme-10-0106 ◽

2011 ◽

Vol 47 (1) ◽

pp. 13-21 ◽

Cited By ~ 49

Author(s):

Qun Cheng ◽

Weipin Dong ◽

Lei Qian ◽

Jingcheng Wu ◽

Yongde Peng

Keyword(s):

Cell Proliferation ◽

Protein Kinase ◽

Signaling Pathways ◽

Cell Line ◽

Cell Apoptosis ◽

Mitogen Activated Protein Kinase ◽

Pancreatic Β Cell ◽

Β Cell ◽

Mitogen Activated Protein ◽

Phosphoinositide 3 Kinase

Visfatin is an adipocytokine that plays an important role in attenuating insulin resistance by binding to insulin receptor. It has been suggested that visfatin plays a role in the regulation of cell apoptosis and inflammation by an as yet unidentified mechanism. This study investigated the protective effects of visfatin on palmitate-induced islet β-cell apoptosis in the clonal mouse pancreatic β-cell line MIN6. The cells were treated with palmitate and/or recombinant visfatin. An 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan assay was used to detect cell proliferation, V-FITC/propidium iodide staining was used to measure cell apoptosis and necrosis, and western blot analysis was used to detect the expression of proapoptotic proteins. The incubation of the cells with visfatin led to a concentration-dependent increase of cell proliferation (1.55-fold at 10−7 M and 24 h compared with control,P<0.05). Visfatin significantly reduced the cell apoptosis induced by palmitate and caused a significant change in the expression of several proapoptotic proteins, including upregulation of Bcl-2 and a marked downregulation of cytochromecand caspase 3. Visfatin also activated the ERK1/2 and the phosphoinositide 3-kinase (PI3K)/AKT signaling pathways in a time- and concentration-dependent manner, and the effect of visfatin on apoptosis was blocked by the specific ERK1/2 and PI3K/AKT inhibitors, PD098059 and LY294002. We conclude that visfatin can increase β-cell proliferation and prevent apoptosis, activate intracellular signaling, and regulate the expression of proapoptotic proteins. The antiapoptotic action of visfatin is mediated by activation of mitogen-activated protein kinase-dependent and PI3K-dependent signaling pathways.

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