Báo cáo khoa học: Gonadotropin-releasing hormone and ovarian cancer: a functional and mechanistic overview

Gonadotropin-releasing Hormone and Ovarian Cancer: A Functional and Mechanistic Overview

Tác giả: Wai-Kin So, Jung-Chien Cheng, Song-Ling Poon, Peter C. K. Leung

Lĩnh vực: Sản phụ khoa, Ung thư học

Nội dung tài liệu: Tài liệu này là một bài tổng quan (mini-review) xem xét vai trò của hormone giải phóng gonadotropin (GnRH) và thụ thể GnRH trong ung thư biểu mô buồng trứng. Bài viết tập trung vào các tác động chống tăng sinh của các chất tương tự GnRH, cơ chế phân tử liên quan, cũng như các quan sát gần đây về ảnh hưởng của GnRH lên quá trình apoptosis và di chuyển của tế bào ung thư buồng trứng. Nghiên cứu cũng thảo luận về các ứng dụng lâm sàng tiềm năng của các chất tương tự GnRH trong điều trị ung thư buồng trứng.

Mục lục chi tiết:

• MINIREVIEW
• Gonadotropin-releasing hormone and ovarian cancer: a functional and mechanistic overview
• Keywords
• Correspondence
• The hypothalamic decapeptide gonadotropin-releasing hormone (GnRH) is well known for its role in the control of pituitary gonadotropin secretion, but the hormone and receptor are also expressed in extrapituitary tissues and tumor cells, including epithelial ovarian cancers. It is hypothesized that they may function as a local autocrine regulatory system in nonpituitary contexts. Numerous studies have demonstrated a direct antiproliferative effect on ovarian cancer cell lines of GnRH and its synthetic analogs. This effect appears to be attributable to multiple steps in the GnRH signaling cascade, such as cell cycle arrest at G0/G1. In contrast to GnRH signaling in pituitary gonadotropes, the involvement of Gαq, protein kinase C and mitogen-activated protein kinases is less apparent in neoplastic cells. Instead, in ovarian cancer cells, GnRH receptors appear to couple to the pertussis toxin-sensitive protein Gαi, leading to the activation of protein phosphatase, which in turn interferes with growth factor-induced mitogenic signals. Apoptotic involvement is still controversial, although GnRH analogs have been shown to protect cancer cells from doxorubicin-induced apoptosis. Recently, data supporting a regulatory role of GnRH analogs in ovarian cancer cell migration/invasion have started to emerge. In this mini-review, we summarize the current understanding of the antiproliferative actions of GnRH analogs, as well as the recent observations of GnRH effects on ovarian cancer cell apoptosis and motogenesis. The molecular mechanisms that mediate GnRH actions and the clinical applications of GnRH analogs in ovarian cancer patients are also discussed.
• Gonadotropin theory of ovarian cancer
• Abbreviations
• GnRH and ovarian cancer
• GnRH/GnRH receptor autocrine system in ovarian cancer cells
• Antiproliferative effect of GnRH analogs on ovarian cancer
• Table 1. In vitro effects of GnRH-I and GnRH-II analogs on OSE and ovarian cancer cell lines. R-I, GnRH-I receptor; R-II, GnRH-II receptor; ND, not determined; DOX, doxorubicin; +, positive; -, negative. Expression of GnRH receptors is based on reports published by individual groups.
• Table 1. (Continued)
• Table 2. Overview of trials using GnRH agonists in ovarian cancer. CR, complete response; PR, partial response; SD, stable disease.
• Fig. 1. GnRH-I signaling in ovarian cancer cells. (A) Through Gαi, GnRH-I analogs activate PTP to dephosphorylate EGFR and abolish EGF-induced ERK activation, c-fos expression and proliferation. (B) Gβγ subunit activates ERK and mediates GnRH-I-induced growth inhibition. (C) GnRH-I activates ERK through a PKC-dependent or PKC-independent pathway to inhibit proliferation. (D) GnRH-I activates JNK, which increases AP-1 activity and JunD-DNA binding to extend the cell cycle. (E) GnRH-I suppresses apoptosis through activation of PP2A. (F) GnRH-I stimulates NF-κB activity and nuclear translocation to protect ovarian cancer cells from apoptosis. (G) GnRH-I acts through Gαi to counteract forskolin (FK)-induced cAMP. The presence of a functional GnRH-II receptor has yet to be evaluated. Dashed arrows represent the EGF-stimulated mitogenic signaling pathway; FS, forskolin; AC; adenylate cyclase.
• Fig. 2. GnRH-II signaling in ovarian cancer cells. (A) Similar to GnRH-I, GnRH-II activates PTP to inhibit EGF-induced ERK activation, c-fos expression and proliferation. (B) Through PKC, GnRH-II activates ERK and Elk-1 to suppress proliferation. (C) GnRH-II activates JNK to induce migration/invasion. (D) GnRH-II activates Gαi or p38 and AP-1 to induce apoptosis. Dashed arrows represent the EGF-stimulated mitogenic signaling pathway.
• Signaling and mechanism of GnRH action in ovarian cancer cells
• Clinical studies on GnRH agonists and antagonists in ovarian cancer
• Conclusions and future prospects
• Acknowledgements
• References