Biology of the gonadotropin-releasing hormone system in gynecological cancers.
The expression of GnRH and its receptor as a part of an autocrine regulatory system of cell proliferation has been demonstrated in a number of human malignant tumors, including cancers of the breast, ovary and endometrium. Dose-dependent antiproliferative effects of GnRH agonists in cell lines derived from these cancers have been observed by various investigators. GnRH antagonists also have marked antiproliferative activity in most breast, ovarian and endometrial cancer cell lines tested, indicating that the dichotomy of GnRH agonists and antagonists might not apply to the GnRH system in cancer cells. The classical GnRH receptor signal-transduction mechanisms, known to operate in the pituitary, are not involved in the mediation of antiproliferative effects of GnRH analogs in cancer cells. Rather, the GnRH receptor interacts with the mitogenic signal transduction of growth factor receptors and related oncogene products associated with tyrosine kinase activity, via activation of a phosphotyrosine phosphatase, resulting in downregulation of cancer cell proliferation. In addition, GnRH activates nuclear factor kappaB and protects the cancer cells from apoptosis. Furthermore, GnRH induces activation of the c-Jun N-terminal kinase/activator protein-1 (AP-1) pathway independent of the known AP-1 activators, protein kinase or mitogen activated protein kinase.
Gründker
Carsten
C
Department of Gynecology and Obstetrics, Georg-August-University of Göttingen, Robert-Koch-Strasse 40, D-37070 Göttingen, Germany.
Günthert
Andreas R
AR
Westphalen
Silke
S
Emons
Günter
G
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D005260:Female; D005833:Genital Neoplasms, Female / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D011966:Receptors, LHRH / Q000819:agonists / Q000096:biosynthesis
D018931:Antineoplastic Agents, Hormonal; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone