title: Treatment with anticancer agents induces dysregulation of specific Wnt signaling pathways in human ovarian luteinized granulosa cells in vitro.
abstract: Chemotherapy has been associated with premature ovarian failure and infertility in women with cancer. It is well known that anticancer drugs reduce the primordial follicle pool and harm the ovarian blood vascularization leading to ovarian atrophy. However, their mechanism of injury still remains unclear. The aim of this study was to identify the cellular mechanisms involved in the toxicity of chemotherapy drugs belonging to different classes on human ovarian luteinized granulosa cells (LGCs). Treatment with doxorubicin (DXR), paclitaxel (PC), and cisplatin (CP) affected LGCs viability by inducing apoptosis and downregulating both estrogen receptor β and follicle-stimulating hormone receptor in a dose-dependent manner. Several members of the WNT signaling pathway are expressed in granulosa cells where they regulate follicle development, ovulation, and luteinization. Here we show that treatment with DXR, PC, and CP induced upregulation of WNT4 expression, whereas WNT3 expression was downregulated by DXR and PC and upregulated by CP. Analysis of the WNT3 downstream signaling pathway showed that total β-catenin protein levels were reduced upon treatment with DXR and PC. Additionally, restoration of β-catenin signaling by lithium chloride protected LGCs from the injury induced by chemotherapy. The in vitro LGC toxicity model described might represent a tool to identify components of specific signaling pathways, such as the Wnt pathway, that can be targeted in order to limit the follicular damage caused by chemotherapy.
authors: * Reproductive Sciences Lab, Division of Genetics and Cell Biology, and.
authors: Ana Maria
authors: AM
authors: Sanchez
authors: Veronica
authors: V
authors: Giorgione
authors: Paola
authors: P
authors: Viganò
authors: Enrico
authors: E
authors: Papaleo
authors: Massimo
authors: M
authors: Candiani
authors: Giorgia
authors: G
authors: Mangili
authors: Paola
authors: P
authors: Panina-Bordignon
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D047629:Estrogen Receptor beta / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006107:Granulosa Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology; D034461:Luteinization; D017239:Paclitaxel / Q000494:pharmacology; D011962:Receptors, FSH / Q000187:drug effects / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D060508:Wnt3 Protein / Q000378:metabolism; D060528:Wnt4 Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047629:Estrogen Receptor beta; D011962:Receptors, FSH; C555507:WNT3 protein, human; C555581:WNT4 protein, human; D060508:Wnt3 Protein; D060528:Wnt4 Protein; D004317:Doxorubicin; D018021:Lithium Chloride; D017239:Paclitaxel; D002945:Cisplatin
keywords: chemotherapy; granulosa cells.; reproductive toxicity