Increase of doxorubicin-induced apoptosis after knock-down of gonadotropin-releasing hormone receptor expression in human endometrial, ovarian and breast cancer cells.
The majority of human endometrial, ovarian and breast cancers express receptors for gonadotropin-releasing hormone (GnRH). Their proliferation is time- and dose-dependently reduced by GnRH and its agonistic analogs. GnRH agonists inhibit the mitogenic signal transduction of growth factor receptors via activation of a phosphotyrosine phosphatase, resulting in downregulation of cancer cell proliferation. Induction of apoptosis is not involved. Recently we showed that the GnRH agonist triptorelin induces activation of nuclear factor-kappaB (NFkappaB) and thus reduces the apoptosis induced by the cytotoxic agent doxorubicin in human endometrial and ovarian cancer cells. The triptorelin-induced reduction of doxorubicin-induced apoptosis was blocked by inhibition of NFkappaB translocation into the nucleus. The present study was conducted to investigate whether knock-down of GnRH receptor expression reduces GnRH agonist-induced anti-apoptotic action. We show that knock-down of GnRH receptor expression results in an increase of doxorubicin-induced apoptosis in human endometrial and ovarian cancers and in the human breast cancer cell line MCF-7. These data further demonstrate that GnRH agonists suppress chemotherapeutic drug-induced apoptosis via activation of the GnRH receptor in these cancers. The situation is different with T-47-D breast cancer cells. After knock-down of GnRH receptor expression doxorubicin-induced apoptosis was decreased, indicating that GnRH agonists do not suppress chemotherapeutic drug-induced apoptosis in T-47-D breast cancer cells.
Fister
Stefanie
S
Department of Gynecology and Obstetrics, Georg-August-University, Göttingen, Germany.
Schlotawa
Lars
L
Günthert
Andreas R
AR
Emons
Günter
G
Gründker
Carsten
C
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D004336:Drug Antagonism; D016889:Endometrial Neoplasms / Q000188:drug therapy*; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists / Q000494:pharmacology; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D011966:Receptors, LHRH / Q000187:drug effects*; D017329:Triptorelin Pamoate / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D011966:Receptors, LHRH; D017329:Triptorelin Pamoate; D007987:Gonadotropin-Releasing Hormone; D004317:Doxorubicin