Reproductive Hormone-Induced, STAT3-Mediated Interleukin 6 Action in Normal and Malignant Human Ovarian Surface Epithelial Cells

Syed, Viqar; Ulinski, Gregory; Mok, Samuel C.; Ho, Shuk Mei

doi:10.1093/jnci/94.8.617

Cited by 129 publications

(102 citation statements)

References 62 publications

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“…Additionally, FSH significantly upregulates the level of protein kinase Cα (PKCα) mRNA and protein, and the PKC pathway has been proposed to play a role in FSH-induced cell proliferation in ovarian cancer cells [27]. FSH also stimulates the growth of human OSE and ovarian cancer cells through the PKA and inerleukin-6/signal transducers and activators of transcription 3 (STAT3) signaling pathway [45]. The present study shows that FSH stimulated survivin expression through activation of the PI3K/AKT signal transduction pathway in SKOV-3 and ES-2 cells.…”

Section: Discussionmentioning

confidence: 99%

Activation of the PI3K/AKT pathway mediates FSH-stimulated VEGF expression in ovarian serous cystadenocarcinoma

et al. 2008

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There is evidence to suggest that follicle-stimulating hormone (FSH) can facilitate the neovascularization of ovarian cancers by increasing vascular endothelial growth factor (VEGF) expression in cancer cells, although the underlying molecular mechanism of this process is not well known. Therefore, we investigated the effect of FSH on VEGF expression in the ovarian cancer cell lines SKOV-3 and ES-2. Treatment with FSH significantly increased VEGF expression in a dose-and time-dependent manner. In addition, FSH treatment enhanced the expression of survivin and hypoxiainducible factor-1 (HIF-1α). Knockdown of survivin or HIF-1α suppressed VEGF expression, but only knockdown of survivin inhibited FSH-stimulated VEGF expression. Pretreatment with LY294002, a phosphoinositide 3-kinase (PI3K)/AKT inhibitor, neutralized the enhanced expression of survivin induced by FSH, but treatment with U0126, a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor, had no such effect. We further showed that ovarian serous cystadenocarcinoma samples had much higher incidence of positive AKT and phosphorylated AKT (pAKT) protein staining than did benign ovarian cystadenoma samples (p < 0.01). The 5-year survival rate was only about 15% in patients with ovarian serous cystadenocarcinoma who had AKT and pAKT expression, whereas it was about 80% in those who did not have AKT or pAKT expression. Taken together, these results indicate that FSH increases the expression of VEGF by upregulating the expression of survivin, which is activated by the PI3K/AKT signaling pathway. Understanding the role of the PI3K/AKT pathway in FSH-stimulated expression of survivin and VEGF will be beneficial for evaluating the prognosis for patients with ovarian serous cystadenocarcinoma and for pursuing effective treatment against this disease.

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Section: Discussionmentioning

confidence: 99%

Activation of the PI3K/AKT pathway mediates FSH-stimulated VEGF expression in ovarian serous cystadenocarcinoma

et al. 2008

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“…Serum added to the bottom chamber was used as the chemoattractant. At 24 hours after plating, noninvading cells were removed, and invading cells were counted in 5 fields per slide as previously described (37). The assay was run in triplicate.…”

Section: Invasion Assaymentioning

confidence: 99%

“…Cellular extracts were prepared as previously described (37). Briefly, cell lysates were prepared in radioimmunoprecipitation assay buffer, and proteins extracted (20 mg) from each cell culture were separated by electrophoresis on 7.5% or 10% SDS-polyacrylamide gels.…”

Section: Western Blottingmentioning

confidence: 99%

Progesterone and 1,25-Dihydroxyvitamin D3 Inhibit Endometrial Cancer Cell Growth by Upregulating Semaphorin 3B and Semaphorin 3F

Nguyen

Ivanova

Kavandi

et al. 2011

Molecular Cancer Research

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Class 3 semaphorins (SEMA), SEMA3B and SEMA3F, are secreted proteins that regulate angiogenesis, tumor growth, and metastasis by binding to their transmembrane receptor complex consisting of plexins and neuropilins (NP). Expression of SEMAs and their receptors was assessed in tissue microarrays by immunohistochemistry. SEMA3B, SEMA3F, and plexin A3 were expressed strongly in normal endometrial tissues, whereas grade-dependent decreases were found in endometrial carcinomas.

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“…Results of multiple studies indicate a pathogenic role of this cytokine in the malignant transformation, progression and chemotherapy resistance of OVCA (Syed et al 2002, Nilsson et al 2005, Rabinovich et al 2007, Yang et al 2009, Wang et al 2010a, 2012. Recently, the results of our studies indicated that IL6 secreted by OVCA cells may contribute to the refractoriness of these cells to TAM via ER isoforms and steroid hormone receptor coactivator (SRC)-1 (Wang et al 2014).…”

Section: Introductionmentioning

confidence: 77%

“…In addition, increased activation of their downstream targets ERK and PI3K/Akt leading to increased pERa-Ser118 and/or pERa-Ser167 have been observed (Gee et al 2001, Yamashita et al 2005, Sarwar et al 2006. It has been widely reported that IL6 plays a critical role in the development and progression of OVCA (Syed et al 2002, Nilsson et al 2005, Rabinovich et al 2007, Yang et al 2009, Wang et al 2012. Recent results from our group indicated that IL6 secreted by OVCA cells may contribute to the refractoriness of these cells to TAM via ER isoforms and SRC-1 (Wang et al 2014).…”

Section: Discussionmentioning

confidence: 98%

IL6 induces TAM resistance via kinase-specific phosphorylation of ERα in OVCA cells

Wang

Niu

Guo

et al. 2015

Journal of Molecular Endocrinology

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About 40-60% of ovarian cancer (OVCA) cases express ERa, but only a small proportion of patients respond clinically to anti-estrogen treatment with estrogen receptor (ER) antagonist tamoxifen (TAM). The mechanism of TAM resistance in the course of OVCA progression remains unclear. However, IL6 plays a critical role in the development and progression of OVCA. Our recent results indicated that IL6 secreted by OVCA cells may promote the resistance of these cells to TAM via ER isoforms and steroid hormone receptor coactivator-1. Here we demonstrate that both exogenous (a relatively short period of treatment with recombinant IL6) and endogenous IL6 (generated as a result of transfection with a plasmid encoding sense IL6) increases expression of pERa-Ser118 and pERa-Ser167 in non-IL6-expressing A2780 cells, while deleting endogenous IL6 expression in IL6-overexpressing CAOV-3 cells (by transfection with a plasmid encoding antisense IL6) reduces expression of pERa-Ser118 and pERa-Ser167, indicating that IL6-induced TAM resistance may also be associated with increased expression of pERa-Ser118 and pERa-Ser167 in OVCA cells. Results of further investigation indicate that IL6 phosphorylates ERa at Ser118 and Ser167 by triggering activation of MEK/ERK and phosphotidylinositol 3 kinase/Akt signaling, respectively, to activate the ER pathway and thereby induce OVCA cells resistance to TAM. These results indicate that IL6 secreted by OVCA cells may also contribute to the refractoriness of these cells to TAM via the crosstalk between ER and IL6-mediated intracellular signal transduction cascades. Overexpression of IL6 not only plays an important role in OVCA progression but also promotes TAM resistance. Our results indicate that TAM-IL6-targeted adjunctive therapy may lead to a more effective intervention than TAM alone.Key Words

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Reproductive Hormone-Induced, STAT3-Mediated Interleukin 6 Action in Normal and Malignant Human Ovarian Surface Epithelial Cells

Abstract: The IL-6/STAT3 signaling pathway may mediate FSH-, LH-, and estrogen-stimulated HOSE cell proliferation. Increased IL-6Ralpha expression and constitutive STAT3 activation may be associated with ovarian cancer.

Cited by 129 publications

References 62 publications

Activation of the PI3K/AKT pathway mediates FSH-stimulated VEGF expression in ovarian serous cystadenocarcinoma

Activation of the PI3K/AKT pathway mediates FSH-stimulated VEGF expression in ovarian serous cystadenocarcinoma

Progesterone and 1,25-Dihydroxyvitamin D3 Inhibit Endometrial Cancer Cell Growth by Upregulating Semaphorin 3B and Semaphorin 3F

IL6 induces TAM resistance via kinase-specific phosphorylation of ERα in OVCA cells

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