Treatment with anticancer agents induces dysregulation of specific Wnt signaling pathways in human ovarian luteinized granulosa cells in vitro.

نویسندگان

  • Ana Maria Sanchez
  • Veronica Giorgione
  • Paola Viganò
  • Enrico Papaleo
  • Massimo Candiani
  • Giorgia Mangili
  • Paola Panina-Bordignon
چکیده

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.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Evidence for an association between Wnt-independent -catenin intracellular localization and ovarian apoptotic events in normal and PCO-induced rat ovary

The association of secreted frizzled related protein type 4 (Sfrp4) as an antagonist of Wnt mole-cules in apoptotic events has been reported previously. Moreover, its increased expression has been reported in the ovary of women with polycystic ovary (PCO). We have demonstrated in-creased Sfrp4 in PCO-induced rat ovary related to an increased number of apoptotic follicles showing nuclear ?cateni...

متن کامل

P-58: Secreted Frizzeled Related Protein Type-4as an Inducer of Apoptosis and Terminal Differentiationof Rat Granulosa Cells

Background: Involvement of Wnt proteins and one of its antagonist known as secreted Frizzled Related Protein type-4 (sFPRP-4) was reported in rodent ovarian follicular development. Other studies showed an ap- Abstracts of the 11th Royan International Congress on Reproductive Biomedicine 7 7 International Journal of Fertility & Sterility (IJFS), Vol 4, Suppl 1, Summer 2010 optotic-associated exp...

متن کامل

Dysregulation of the WNT Signaling Pathway Through Methylation of Wnt Inhibitory Factor 1 and Dickkopf-1 Genes among AML Patients at the Time of Diagnosis

Background: In acute myeloblastic leukemia, a large number of tumor suppressor genes are silenced through DNA methylation such as CDKN2B & p73. Wnt inhibitory factor 1 (WIF1) and Dickkopf-3 (DKK-1) are negative regulators of Wnt signaling pathway. In the present study, we evaluated the methylation status of WIF1 and DKK-1 genes in acute myeloblastic leukemia patients. Patients and Methods: ...

متن کامل

Activation of Wnt signaling reduces high-glucose mediated damages on skin fibroblast cells

Objective(s): High-glucose (HG) stress, a mimic of diabetes mellitus (DM) in culture cells, alters expression of a large number of genes including Wnt and NF-κB signaling-related genes; however, the role of Wnt signaling during HG-mediated fibroblast damage and the relationship between Wnt and NF-κB signaling have not been understood. In this study, we aimed to investigate the ffects of Wnt sig...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Toxicological sciences : an official journal of the Society of Toxicology

دوره 136 1  شماره 

صفحات  -

تاریخ انتشار 2013