Apoptosis-associated signaling pathways are required for chemotherapy-mediated female germ cell destruction
G I Perez1, C M Knudson, L Leykin
1Vincent Center for Reproductive Biology, Massachusetts General Hospital and Department of Obstetrics and Gynecology, Harvard Medical School, Boston 02114, USA.
Abstract:
Female sterility resulting from oocyte destruction is an unfortunate, and in many cases inevitable, consequence of chemotherapy. We show that unfertilized mouse oocytes exposed to therapeutic levels of the antitumor drug, doxorubicin (DXR), undergo apoptosis; however, fertilized oocytes do not initiate apoptosis, but enter cell-cycle arrest, when treated with DXR. Apoptosis induced by DXR in oocytes is blocked by sphingosine-1-phosphate, an inhibitor of ceramide-promoted cell death. Oocytes from Bax-deficient, but not p53-null, female mice display complete resistance to DXR-induced apoptosis in vivo and in vitro. Pretreatment of oocytes with a specific peptide inhibitor of caspases also abrogates the apoptotic response to DXR. These findings indicate that oocyte destruction caused by chemotherapy can be prevented by manipulation of apoptosis-associated signaling pathways.
Insights
Chemotherapy drug doxorubicin (DXR) causes oocyte destruction via apoptosis. However, targeting apoptosis pathways can prevent this chemotherapy side effect, preserving female fertility.
Area of Science:
- Reproductive Biology
- Cancer Therapeutics
- Cell Death Signaling
Background:
- Chemotherapy, including doxorubicin (DXR), can cause female sterility due to oocyte destruction.
- Oocyte apoptosis is a key mechanism leading to chemotherapy-induced infertility.
- Understanding the molecular pathways of oocyte apoptosis is crucial for fertility preservation.
Purpose of the Study:
- To investigate the mechanisms of doxorubicin-induced oocyte apoptosis.
- To identify potential targets for preventing chemotherapy-induced oocyte destruction.
- To differentiate the response of fertilized versus unfertilized oocytes to DXR.
Main Methods:
- Exposure of mouse oocytes (fertilized and unfertilized) to doxorubicin (DXR) in vitro and in vivo.
- Assessment of apoptosis using sphingosine-1-phosphate and caspase inhibitors.
- Analysis of oocyte response in Bax-deficient and p53-null mouse models.
Main Results:
- Unfertilized oocytes undergo apoptosis upon DXR treatment, while fertilized oocytes arrest cell-cycle.
- DXR-induced oocyte apoptosis is mediated by ceramide-dependent pathways and caspases.
- Bax-deficient oocytes are resistant to DXR-induced apoptosis, implicating Bax in the process.
Conclusions:
- Oocyte apoptosis is a significant contributor to chemotherapy-induced female sterility.
- Targeting apoptosis-associated signaling pathways, such as those involving Bax and caspases, can prevent DXR-induced oocyte destruction.
- These findings offer potential strategies for preserving female fertility during cancer treatment.
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