Apoptosis-associated signaling pathways are required for chemotherapy-mediated female germ cell destruction.
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.
Perez
G I
GI
Vincent Center for Reproductive Biology, Massachusetts General Hospital and Department of Obstetrics and Gynecology, Harvard Medical School, Boston 02114, USA.
Knudson
C M
CM
Leykin
L
L
Korsmeyer
S J
SJ
Tilly
J L
JL
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002518:Ceramides / Q000494:pharmacology; D046508:Culture Techniques; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology*; D005260:Female; D007941:Leukemia P388 / Q000188:drug therapy / Q000473:pathology; D008246:Lysophospholipids; D051379:Mice; D009865:Oocytes / Q000187:drug effects*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein
D000590:Amino Acid Chloromethyl Ketones; D000903:Antibiotics, Antineoplastic; C494827:Bax protein, mouse; D002518:Ceramides; D015853:Cysteine Proteinase Inhibitors; D008246:Lysophospholipids; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C060506:sphingosine 1-phosphate; D004317:Doxorubicin; D013110:Sphingosine