Downregulation of autophagy gene expression in endometria from women with polycystic ovary syndrome

Šumarac-Dumanović, Mirjana; Apostolovic, Milica; Janjetović, Kristina; Jeremić, Danka; Popadić, Dušan; Ljubić, Aleksandar; Micić, Jelena; Dukanac-Stamenkovic, Jelena; Tubić, Aleksandra; Stevanović, Darko; Micić, Dragan; Trajkovič, Vladimir

doi:10.1016/j.mce.2016.11.009

Cited by 38 publications

(23 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There is also preliminary evidence showing changes in the expression of autophagy genes in endometria from women with PCOS (Sumarac-Dumanovic et al 2017). This evidence, when combined with our observation of ovarian autophagy activation in human and rats with PCOS, suggests that multiple organ autophagy changes may be a possible factor involved in the development of PCOS and PCOS-related metabolic disorders.…”

Section: Discussionsupporting

confidence: 64%

Autophagy is activated in the ovarian tissue of polycystic ovary syndrome

You

et al. 2018

Reproduction

View full text Add to dashboard Cite

The importance of autophagy in polycystic ovary syndrome (PCOS)-related metabolic disorders is increasingly being recognized, but few studies have investigated the role of autophagy in PCOS. Here, transmission electron microscopy demonstrated that autophagy was enhanced in the ovarian tissue from both humans and rats with PCOS. Consistent with this, ovarian granulosa cells from PCOS rats showed increases in the autophagy marker protein light chain 3B (LC3B), whereas levels of the autophagy substrate SQSTM1/p62 were decreased. In addition, the ratio of LC3-II/LC3-I was markedly elevated in human PCOS ovarian tissue compared with normal ovarian tissue. Real-time PCR arrays indicated that 7 and 34 autophagy-related genes were down- and up-regulated in human PCOS , Signal-Net, and regression analysis suggested that there are a wide range of interactions among these 41 genes, and a potential network based on and may be responsible for autophagy activation in PCOS. Systematic functional analysis of 41 differential autophagy-related genes indicated that these genes are highly involved in specific cellular processes such as response to stress and stimulus, and are linked to four significant pathways, including the insulin, ERBB, mTOR signaling pathways and protein processing in the endoplasmic reticulum. This study provides evidence for a potential role of autophagy disorders in PCOS in which autophagy may be an important molecular event in the pathogenesis of PCOS.

show abstract

Section: Discussionsupporting

confidence: 64%

Autophagy is activated in the ovarian tissue of polycystic ovary syndrome

You

et al. 2018

Reproduction

View full text Add to dashboard Cite

show abstract

“…4A,B). These results are consistent with a previous report using MCF-7 breast cancer cells [47], as well as with the increased foxO1 mRNA levels detected in the endometrial tissue of PCOS patients treated with Met [48]. Since the Eg-agt8 and Eg-atg12 genes possess conserved consensus sequences for the binding of the FoxO transcription factor in the upstream region of their translation initiation codons, it has been considered that they are possible targets of Eg-FoxO [7].…”

Section: A C C E P T E D Msupporting

confidence: 92%

Metformin promotes autophagy in Echinococcus granulosus larval stage

Loos

Nicolao

Cumino

2018

Molecular and Biochemical Parasitology

View full text Add to dashboard Cite

Cystic echinococcosis is a neglected parasitic disease caused by the larval stage of Echinococcus granulosus for which an effective treatment is not yet available. Since autophagy constitutes a homeostatic mechanism during stress, either inhibition or activation of its activity might be detrimental for survival of the parasite. Amongst the critical molecules that regulate autophagy, TOR, AMPK and sirtuins are the best characterized ones. Previously, we have identified the autophagic machinery, the occurrence of TORC1-controlled events, and the correlation between autophagy and the activation of the unfolded protein response in E. granulosus larval stage. In addition, we have demonstrated that the parasite is susceptible to metformin (Met), a drug that indirectly activates Eg-AMPK and induces energy stress. In this work, we demonstrate that Met induces autophagy in the E. granulosus larval stage. Electron microscopy analysis revealed the presence of autophagic structures in Met-treated protoscoleces. In accordance with these findings, the autophagic marker Eg-Atg8 as well as the transcriptional expression of Eg-atg6, Eg-atg8, Eg-atg12 and Eg-atg16 genes were significantly up-regulated in Met-treated parasites. The induction of the autophagic process was concomitant with Eg-foxO over-expression and its nuclear localization, which could be correlated with the transcriptional regulation of this pathway. On the other hand, the expression of Eg-AKT and Eg-Sirts suggests a possible participation of these conserved proteins in the regulation of Eg-FoxO. Therefore, through pharmacological activation of the AMPK-FoxO signaling pathway, Met could play a role in the death of the parasite contributing to the demonstrated anti-echinococcal effects of this drug. The understanding of the regulatory mechanisms of this pathway in E. granulosus represents a solid basis for choosing appropriate targets for new chemotherapeutic agents.

show abstract

“…Taken together, our results suggest that PI3K–Akt–NFκB-induced suppression of inflammation could be one of the key mechanisms through which metformin acts in the uterus. Interestingly, although acute inflammation is likely to induce autophagy in the mouse uterus (Park et al, 2016), and impaired endometrial autophagy has been observed in PCOS patients (Sumarac-Dumanovic et al, 2016), we failed to show that uterine cells capable of mitochondrial-dependent regulation of autophagy as judged by an increase in LC3II protein levels are sensitive to metformin treatment in PCOS-like rats. Further investigations are needed to elucidate if the autophagy contributes to uterine dysfunction under PCOS conditions.…”

Section: Discussionmentioning

confidence: 63%

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

Zhang

Meng

et al. 2017

EBioMedicine

View full text Add to dashboard Cite

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.

show abstract

Downregulation of autophagy gene expression in endometria from women with polycystic ovary syndrome

Cited by 38 publications

References 81 publications

Autophagy is activated in the ovarian tissue of polycystic ovary syndrome

Autophagy is activated in the ovarian tissue of polycystic ovary syndrome

Metformin promotes autophagy in Echinococcus granulosus larval stage

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

Contact Info

Product

Resources

About