Autophagy is upregulated in ovarian endometriosis: a possible interplay with p53 and heme oxygenase-1

Allavena, Giulia; Carrarelli, Patrizia; Bello, Barbara Del; Luisi, Stefano; Petraglia, Felice; Maellaro, Emilia

doi:10.1016/j.fertnstert.2015.02.007

Cited by 76 publications

(83 citation statements)

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“…Here, cargo elements will be hydrolyzed into basic biomolecules, recycled back to the cytosol and reutilized by anabolic pathways to build new proteins and organelles 74 . Recently, autophagy has been shown to be regulated in normal endometrium across the menstrual cycle and to play a relevant role in ovarian endometriosis 75-77 . However, the contribution of autophagy and its therapeutic potential in the development and progression of EC is still underexplored.…”

Section: Discussionmentioning

confidence: 99%

Autophagy orchestrates adaptive responses to targeted therapy in endometrial cancer

et al. 2017

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Targeted therapies in endometrial cancer (EC) using kinase inhibitors rarely result in complete tumor remission and are frequently challenged by the appearance of refractory cell clones, eventually resulting in disease relapse. Dissecting adaptive mechanisms is of vital importance to circumvent clinical drug resistance and improve the efficacy of targeted agents in EC. Sorafenib is an FDA-approved multitarget tyrosine and serine/threonine kinase inhibitor currently used to treat hepatocellular carcinoma, advanced renal carcinoma and radioactive iodine-resistant thyroid carcinoma. Unfortunately, sorafenib showed very modest effects in a multi-institutional phase II trial in advanced uterine carcinoma patients. Here, by leveraging RNA-sequencing data from the Cancer Cell Line Encyclopedia and cell survival studies from compound-based high-throughput screenings we have identified the lysosomal pathway as a potential compartment involved in the resistance to sorafenib. By performing additional functional biology studies we have demonstrated that this resistance could be related to macroautophagy/autophagy. Specifically, our results indicate that sorafenib triggers a mechanistic MAPK/JNK-dependent early protective autophagic response in EC cells, providing an adaptive response to therapeutic stress. By generating in vivo subcutaneous EC cell line tumors, lung metastatic assays and primary EC orthoxenografts experiments, we demonstrate that targeting autophagy enhances sorafenib cytotoxicity and suppresses tumor growth and pulmonary metastasis progression. In conclusion, sorafenib induces the activation of a protective autophagic response in EC cells. These results provide insights into the unopposed resistance of advanced EC to sorafenib and highlight a new strategy for therapeutic intervention in recurrent EC.

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Section: Discussionmentioning

confidence: 99%

Autophagy orchestrates adaptive responses to targeted therapy in endometrial cancer

et al. 2017

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“…Decreased expression of the HO-1 enzyme does not allow the final byproduct of heme breakdown, bilirubin, to form, and its antioxidant capacity is missing in these women. Moreover, a recent study [90] proposed another role of OH-1 in endometriosis pathophysiology. Significantly increased OH-1 levels were observed in endometriomas compared to eutopic endometrial tissue of endometriosis and non-endometriosis patients.…”

Section: Iron and Endometriosismentioning

confidence: 99%

“…Autophagy is a catabolic defensive mechanism in which macromolecules are confiscated and subsequently degraded. Wide activation of autophagy is lethal to the cells, resulting in autophagic cell death [90].…”

Section: Iron and Endometriosismentioning

confidence: 99%

Targeting oxidative stress to treat endometriosis

Harlev

Gupta

Agarwal

2015

Expert Opinion on Therapeutic Targets

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“…The mRNA level of autophagy-related genes (LC3, BECN1) showed significant upregulation in ovarian endometriomas [30]. Loss of autophagy-related gene BECN1 or ATG7 within the perinatal ovary could result in the premature loss of female germ cells [31].…”

Section: Following Insulin Treatment the Imbalance Of Autophagy Was mentioning

confidence: 99%

High insulin impaired ovarian function in early pregnant mice and the role of autophagy in this process

et al. 2017

Endocr J

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METABOLIC DISORDERS, such as PCOS (polycystic ovary syndrome) and T2DM (type 2 diabetes mellitus), are reported to be associated with high miscarriage rates, decreased pregnancy rates, and low live birth rates [1]. PCOS and T2DM are characterized by hyperinsulinemia [2]. PCOS is an endocrine and metabolic disorder with a prevalence ranging from 5 to 13% in women of reproductive age. Moreover, PCOS is often accompanied by menstrual dysfunction, anovulaHigh insulin impaired ovarian function in early pregnant mice and the role of autophagy in this process Abstract. Metabolic disorders, such as PCOS (polycystic ovarian syndrome) and T2DM (type 2 diabetes mellitus), are associated with menstrual dysfunction, anovulation, infertility, and early pregnancy loss. Ovarian dysfunction is not only related to low pregnancy rates but also to the increased risk of miscarriage. Women with PCOS or T2DM, characterized by hyperinsulinemia, commonly experience ovarian dysfunction. In this study, we first explored whether high insulin levels directly affected ovarian functioning during embryo implantation. Mice in the insulin-treated group were given a subcutaneous injection of human recombinant insulin. After insulin treatment, serum levels of E2 (estrogen), PROG (progesterone), LH (luteinizing hormone), and FSH (follicle-stimulating hormone) were obviously lower, and there was a significant decrement of ovarian GDF9 (growth differentiation factor 9) mRNA. H&E (hematoxylin and eosin) staining showed a greater number of immature follicles and less luteinization in the insulin group. Further autophagy was studied in this process. A significant increase of P62 (SQSTM1/Sequestosome1) and a decrease of Cathepsin B, BECN1 (Beclin 1), and ULK1 (Unc-51-like kinase 1) mRNA in ovary was found in the insulin group. Western blot analysis showed that the expressions of LC3 (microtubule-associated protein 1 light chain 3), BECN1, and Cathepsin B proteins in ovaries from insulin group were obviously reduced, while P62 proteins were significantly increased. All these results illustrated that insulin could directly impair ovarian function during embryo implantation and the imbalance of ovarian autophagy due to insulin. Autophagy could enhance the impaired ovarian function results from insulin.

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Autophagy is upregulated in ovarian endometriosis: a possible interplay with p53 and heme oxygenase-1

Cited by 76 publications

References 50 publications

Autophagy orchestrates adaptive responses to targeted therapy in endometrial cancer

Autophagy orchestrates adaptive responses to targeted therapy in endometrial cancer

Targeting oxidative stress to treat endometriosis

High insulin impaired ovarian function in early pregnant mice and the role of autophagy in this process

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