Pigment epithelium‐derived factor increases in type 2 diabetes after treatment with metformin

Akın, Şafak; Aksoy, Duygu Yazgan; Çınar, Neşe; Aydín, Kadriye; Karaağaoğlu, Ergün; Arıyürek, M.; Gülçelik, Neşe Ersöz; Usman, Aydan; Gürlek, Alper

doi:10.1111/j.1365-2265.2012.04341.x

Cited by 19 publications

(15 citation statements)

References 26 publications

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“…The other candidate, the antidiabetic drug Metformin, exerts an antiproliferative effect on the endometrium of tamoxifen-treated mice via inhibition of mTOR (47). Interestingly, Metformin increases PEDF levels in patients with type II diabetes (48), and our data demonstrated that rPEDF decreased the activity of PI3K/AKT/mTOR pathway. However, inhibition of PEDF by Metformin was described (49), thus further research is needed to fully comprehend the connection among these observations.…”

Section: Discussionmentioning

confidence: 51%

Pigment Epithelium–Derived Factor Alleviates Tamoxifen-Induced Endometrial Hyperplasia

Goldberg

Bar‐Joseph

Grossman

et al. 2015

Molecular Cancer Therapeutics

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Tamoxifen is a cornerstone component of adjuvant endocrine therapy for patients with hormone-receptor-positive breast cancer. Its significant adverse effects include uterine hyperplasia, polyps, and increased risk of endometrial cancer. However, the underlying molecular mechanism remains unclear. Excessive angiogenesis, a hallmark of tumorigenesis, is a result of disrupted balance between pro-and anti-angiogenic factors. VEGF is a proangiogenic factor shown to be elevated by tamoxifen in the uterus. Pigment epithelium-derived factor (PEDF) is a potent anti-angiogenic factor that suppresses strong pro-angiogenic factors, such as VEGF. Our aim was to investigate whether angiogenic balance plays a role in tamoxifen-induced uterine pathologies, elucidate the molecular impairment in that network, and explore potential intervention to offset the proposed imbalance elicited by tamoxifen. Using in vivo mouse models, we demonstrated that tamoxifen induced a dose-dependent shift in endogenous uterine angiogenic balance favoring VEGF over PEDF. Treatment with recombinant PEDF (rPEDF) abrogated tamoxifen-induced uterine hyperplasia and VEGF elevation, resulting in reduction of blood vessels density. Exploring the molecular mechanism revealed that tamoxifen promoted survival and malignant transformation pathways, whereas rPEDF treatment prevents these changes. Activation of survival pathways was decreased, demonstrated by reduction in AKT phosphorylation concomitant with elevation in JNK phosphorylation. Estrogen receptor-a and c-Myc oncoprotein levels were reduced. Our findings provide novel insight into the molecular mechanisms tamoxifen induces in the uterus, which may become the precursor events of subsequent endometrial hyperplasia and cancer. We demonstrate that rPEDF may serve as a useful intervention to alleviate the risk of tamoxifen-induced endometrial pathologies.

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Section: Discussionmentioning

confidence: 51%

Pigment Epithelium–Derived Factor Alleviates Tamoxifen-Induced Endometrial Hyperplasia

Goldberg

Bar‐Joseph

Grossman

et al. 2015

Molecular Cancer Therapeutics

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“…This is supported by a previous study showing that metformin treatment of patients with newly diagnosed diabetes is associated with a significant increase in serum PEDF level. 20 A great deal of evidence links PEDF to tumor suppression. Besides inhibiting tumor angiogenesis, exogenous or naturally secreted PEDF also induces the differentiation of cancer cells to a less-malignant phenotype, 26,27 which provided the first suggestion that PEDF could reduce malignant phenotype and act directly on tumors.…”

Section: Discussionmentioning

confidence: 99%

“…19 Interestingly, it has been reported that patients with newly diagnosed type 2 diabetes who are taking metformin present higher serum levels of PEDF than those not on metformin. 20 Thus, we hypothesized that the antitumorigenic effects of metformin are mediated through upregulation of PEDF expression in prostate cancer cells. To test this hypothesis, we investigated the effects of metformin on prostate cancer cells and their underlying mechanisms, particularly the involvement of PEDF, both in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

Metformin inhibits prostate cancer cell proliferation, migration, and tumor growth through upregulation of PEDF expression

Chen

et al. 2016

Cancer Biology & Therapy

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Metformin has been reported to inhibit the growth of various types of cancers, including prostate cancer. Yet the mode of anti-cancer action of metformin and the underlying mechanisms remain not fully elucidated. We hypothesized that the antitumorigenic effects of metformin are mediated through upregulation of pigment epithelium-derived factor (PEDF) expression in prostate cancer cells. In this report, metformin treatment significantly inhibited the proliferation and colony formation of prostate cancer cells, in a dose-and time-dependent manner. Meanwhile, Metformin markedly suppressed migration and invasion and induced apoptosis of both LNCaP and PC3 cancer cells. Metformin also reduced PC3 tumor growth in BALB/c nude mice in vivo. Furthermore, metformin treatment was associated with higher PEDF expression in both prostate cancer cells and tumor tissue. Taken together, metformin inhibits prostate cancer cell proliferation, migration, invasion and tumor growth, and these activities are mediated by upregulation of PEDF expression. These findings provide a novel insight into the molecular functions of metformin as an anticancer agent.Abbreviations: PEDF, pigment epithelium-derived factor; AMPK, 5 0 -AMP-activated protein kinase; mTOR, mammalian target of rapamycin; IL8, interleukin8; MAPK, mitogen-activated protein kinase; Met, metformin; qPCR, quantitative polymerase chain reaction; PBS, fetal bovine serum; CCK8, Cell Counter Kit-8; PBS, phosphate-buffered saline solution; PtdIns, propidium iodide; SD, standard deviation

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“…The vital role of PEDF in diabetic retinopathy has been documented by blocking retinal neovascularization and protecting neural actions on photoreceptors and retinal ganglion cells [11]. Moreover, previous studies have also found that PEDF may play a potentially protective role against tubular injury in diabetic nephropathy by attenuating the deleterious effects of advanced glycation end products via the downregulation of RAGE expression [12,13]. Recently, research has revealed that PEDF can inhibit vascular inflammation [14] and occlusive thrombus formation by blocking platelet activation and aggregation [15] through its anti-inflammatory and anti-oxidative properties [16,17].…”

Section: Introductionmentioning

confidence: 99%

The Association Study of Plasma Levels of Pigment Epithelium-Derived Factor with Acute Coronary Syndrome in the Chinese Han Population

et al. 2013

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Objects: To investigate the relationship between plasma levels of pigment epithelium-derived factor (PEDF) and acute coronary syndrome (ACS) in the Chinese Han population. Methods: Plasma PEDF levels were measured in 200 consecutive ACS patients and 160 age- and sex-matched healthy control subjects. Logistic regression analysis was performed to determine whether PEDF was an independently protective factor against ACS. All ACS patients were followed up for 6 months and the short-term major adverse cardiovascular events (MACE) were obtained: cardiac death and recurrent angina. Results: The ACS patients showed notably lower plasma PEDF levels relative to the control group (7.31 ± 2.21 vs. 8.44 ± 2.13 μg/ml, respectively, p = 0.001). Logistic regression analysis revealed that PEDF had a significant protective effect against ACS (OR = 0.76, 95% CI 0.623-0.935, p = 0.01). After 6 months of follow-up, we found that the mean PEDF concentration of the patients with short-term MACE was lower than the patients without (6.05 ± 2.18 vs. 7.52 ± 2.07 µg/ml, p = 0.031). The Kaplan-Meier survival curves suggested that patients with plasma PEDF levels <7.00 µg/ml showed a lower survival trend than those in the higher group, but the difference was not significant (p = 0.477). Conclusions: Our study indicates that plasma PEDF levels are significantly lower in ACS patients than in controls, and lower PEDF levels are further associated with adverse cardiac outcomes after ACS.

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Pigment epithelium‐derived factor increases in type 2 diabetes after treatment with metformin

Cited by 19 publications

References 26 publications

Pigment Epithelium–Derived Factor Alleviates Tamoxifen-Induced Endometrial Hyperplasia

Pigment Epithelium–Derived Factor Alleviates Tamoxifen-Induced Endometrial Hyperplasia

Metformin inhibits prostate cancer cell proliferation, migration, and tumor growth through upregulation of PEDF expression

The Association Study of Plasma Levels of Pigment Epithelium-Derived Factor with Acute Coronary Syndrome in the Chinese Han Population

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