EFFECTS OF LHRH-ANALOGS ON MITOGENIC SIGNAL-TRANSDUCTION IN CANCER-CELLS

The expression of luteinizing hormone-releasing hormone (LHRH) and its receptors has been demonstrated in a number of human malignant tumors , including cancers of the breast, ovary, endometrium and prostate. Th ese findings suggest the presence of an autocrine regulatory system ba sed on LHRH. Recent studies in our laboratory have demonstrated that t he function of LHRH produced by ovarian cancer cells is the inhibition of their proliferation. Dose-dependent antiproliferative effects of L HRH-agonists have been observed by several laboratories in cell lines derived from the above cancers. Interestingly, also LHRH-antagonists h ave marked antiproliferative activity in most of the ovarian, breast a nd endometrial cancer cell lines tested so far, indicating that the di chotomy of LHRH-agonists/LHRH-antagonists is not valid for the LHRH-sy stem in cancer cells. In addition, our data suggest that the classical LHRH receptor signal transduction mechanisms known from the pituitary (phospholipase-C, protein kinase C, adenylyl cyclase) are not involve d in the mediation of LHRH effects in cancer cells. Data obtained by s everal groups, including ours, rather suggest that LHRH analogs interf ere with the signal transduction of growth-factor receptors and relate d oncogene products associated with tyrosine-kinase activity. The mech anism of action is probably an LHRH-induced activation of a phosphotyr osine phosphatase, counteracting the effects of receptor associated ty rosine kinase. In our hands, LHRH analogs virtually blocked the EGF-in duced MAP-kinase activity of ovarian and endometrial cancer cells. The pharmacological exploitation of this mechanism might provide promisin g new therapies for these cancers. (C) 1998 Elsevier Science Ltd. All rights reserved.