Metformin modulates PI3K and GLUT4 expression and Akt/PKB phosphorylation in human endometrial stromal cells after stimulation with androgen and insulin

Ferreira, Gustavo Dias; Germeyer, Ariane; Machado, Amanda de Barros; Nascimento, Tadeu Ludwig do; Strowitzki, T.; Brum, Ilma Simoni; Corleta, Helena von Eye; Capp, Edison

doi:10.1016/j.ejogrb.2014.01.009

Cited by 22 publications

(15 citation statements)

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“…We also show that the anti-inflammatory effect of metformin is via the PI3k-Akt-NFκB signaling pathway. Similar to human endometrial stromal cells in vitro (Ferreira et al, 2014, Germeyer et al, 2011, Takemura et al, 2007) and PCOS patient sera in vivo (Victor et al, 2015), we show that treatment with metformin suppresses PI3k–Akt-mediated increases in TNFα , Il1b , Il6 , and Il8 gene expression in the PCOS-like rat uterus. Indeed, metformin is capable of inhibiting uterine Mcp1 and Mmp2 gene expression, which is elevated in PCOS patients (Piltonen et al, 2015, Repaci et al, 2011).…”

Section: Discussionsupporting

confidence: 61%

Metformin Ameliorates Uterine Defects in a Rat Model of Polycystic Ovary Syndrome

Zhang

Meng

et al. 2017

EBioMedicine

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Adult rats treated concomitantly with insulin and human chorionic gonadotropin exhibit endocrine, metabolic, and reproductive abnormalities that are very similar to those observed in polycystic ovary syndrome (PCOS) patients. In this study, we used this rat model to assess the effects of metformin on PCOS-related uterine dysfunction. In addition to reducing androgen levels, improving insulin sensitivity, and correcting the reproductive cycle, metformin treatment induced morphological changes in the PCOS-like uterus. At the molecular and cellular levels, metformin normalized the androgen receptor-mediated transcriptional program and restored epithelial–stromal interactions. In contrast to glucose transport, uterine inflammatory gene expression was suppressed through the PI3K–Akt–NFκB network, but without affecting apoptosis. These effects appeared to be independent of AMPK subunit and autophagy-related protein regulation. We found that when metformin treatment partially restored implantation, several implantation-related genes were normalized in the PCOS-like rat uterus. These results improve our understanding of how metformin rescues the disruption of the implantation process due to the uterine defects that result from hyperandrogenism and insulin resistance. Our data provide insights into the molecular and functional clues that might help explain, at least in part, the potential therapeutic options of metformin in PCOS patients with uterine dysfunction.

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Section: Discussionsupporting

confidence: 61%

Metformin Ameliorates Uterine Defects in a Rat Model of Polycystic Ovary Syndrome

Zhang

Meng

et al. 2017

EBioMedicine

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“…In future research, we will do more experiments to further prove the role of G3BP1 on regulating PI3K/AKT pathway in NSCLC. In addition, in next studies, we will do some more in-depth experiments to rule out other possibilities in regulating AKT phosphorylation, such as growth factors 43 and Notch1. 44 In conclusion, G3BP1 may play a crucial role in activating PI3K/AKT/mTOR signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Elevated expression of G3BP1 associates with YB1 and p‐AKT and predicts poor prognosis in nonsmall cell lung cancer patients after surgical resection

et al. 2019

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Purpose G3BP1 is an RNA‐binding protein and plays roles in regulating signaling pathway. YB‐1 is a DNA/RNA binding protein encoded by YBX1 gene. Phosphorylated AKT (p‐AKT) acts as a pivotal molecule in PI3K/AKT pathway. YB‐1 drives stress granules (SGs) formation by activating G3BP1 translation under diverse conditions. SGs are involved in many different metabolic and signaling pathways which may include PI3K/AKT/mTOR. So far, there has been no report on the relationship between expression of G3BP1, p‐AKT, and YB1 and clinicopathological features/prognosis in surgically resected nonsmall cell lung cancer (NSCLC) patients. Methods In this study, data from TCGA (The Cancer Genome Atlas) were downloaded to investigate the mRNA expression of G3BP1 and YB1 (YBX1) and their correlation in NSCLC. Also, expression of G3BP1, YB1, and p‐AKT proteins was studied using immunohistochemistry in tissue microarrays of NSCLC and in noncancerous lung tissues. Results We found that the mRNA expression of G3BP1 and YB1 was higher in NSCLC tissues (both P < .05), and G3BP1 was positively correlated with YB1 in mRNA level (r = .399, P < .001). Also, expression of G3BP1, YB1, and p‐AKT proteins was higher in NSCLC tissues (all P < .05). And higher expression of G3BP1 and YB1 proteins was seen in patients with clinical stage II and III compared with stage I (both P < .05). Besides, expression of G3BP1 protein had a positive correlation with YB1 and p‐AKT (both P < .05). Moreover, overall survival was shorter in patients with overexpression of G3BP1, YB1, and p‐AKT proteins (all P < .05). Multivariate analysis confirmed that overexpression of G3BP1 protein was an independent poorer prognostic factor for NSCLC patients (P = .039). Conclusion G3BP1 may play a crucial role in activating PI3K/AKT/mTOR pathway. G3BP1 might be served as a novel prognostic biomarker for surgically resected NSCLC patients, which afforded new insights into the study on the mechanism and therapy of NSCLC.

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“…However, the evidence of the effects of metformin on ovarian cancer is still limited and inconclusive. Metformin was introduced into the clinical practice in the 1950s for the treatment of type II diabetes mellitus but presently it is often used for the treatment of other conditions associated with insulin resistance, especially polycystic ovarian syndrome [ 25 , 26 ]. Current studies report positive effects in the treatment of gynecological cancers such as ovarian, endometrial and cervical cancer [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Effect of metformin on apoptosis induction in ovarian cancer cells

Rogalska¹,

Forma²,

Ciesielski³

et al. 2014

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IntroductionOvarian cancer is one of the most difficult problems in gynecologic oncology and the search for new drugs effective in the treatment of this kind of cancer, especially in cases resistant to current forms of therapy, remains a challenging priority.The aim of the studyThe aim of the study was to analyze the effect of metformin on apoptosis and the BIRC5 gene expression in ovarian cancer cell line SKOV-3. The BIRC5 gene encodes survivin protein.Material and methodsSKOV-3 cells were treated with metformin (10 mM). Apoptotic changes in studied cells were analyzed by double staining using a mixture of fluorochromes – Hoechst 33258/propidium iodide (PI). The expression of the BIRC5 gene at the mRNA level was analyzed using the real-time PCR technique.ResultsTreatment of cells with metformin causes changes in the cell shape from oval to spindle and leads to the separation of the cells from the monolayer. Furthermore, metformin induces apoptosis and necrosis of ovarian cancer cells. A statistically significant increase in the number of apoptotic cells after 48 and 72 hours’ treatment with metformin relative to a control cells seems to be correlated with a decrease in the expression of the BIRC5 gene at the mRNA level.ConclusionsMetformin seems to be a promising agent, whose use in ovarian cancer patients may contribute to improving the effectiveness of therapy.

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Metformin modulates PI3K and GLUT4 expression and Akt/PKB phosphorylation in human endometrial stromal cells after stimulation with androgen and insulin

Cited by 22 publications

References 50 publications

Metformin Ameliorates Uterine Defects in a Rat Model of Polycystic Ovary Syndrome

Metformin Ameliorates Uterine Defects in a Rat Model of Polycystic Ovary Syndrome

Elevated expression of G3BP1 associates with YB1 and p‐AKT and predicts poor prognosis in nonsmall cell lung cancer patients after surgical resection

Effect of metformin on apoptosis induction in ovarian cancer cells

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