Gonadotropin-releasing hormone analog structural determinants of selectivity for inhibition of cell growth: Support for the concept of ligand-induced selective signaling
Gonadotropin-releasing hormone analog structural determinants of selectivity for inhibition of cell growth: Support for the concept of ligand-induced selective signaling
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DOI：
10.1210/me.2006-0537
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发表时间：
2008-07-01
影响因子：
--
通讯作者：
Millar, Robert P.
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文献类型：
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作者：
de Maturana, Rakel Lopez;Pawson, Adam J.;Millar, Robert P.
GnRH及其受体在人类生殖道癌中表达，GnRH类似物在癌细胞株中已被证实具有直接的抗增殖作用。负责这一作用的细胞内信号不同于调节垂体促性腺激素分泌的信号。两种作用的GnRH构效关系不同。在此，我们报道了GnRH激动剂在大鼠模型细胞系统中的抗增殖作用以及在HEK293细胞中稳定表达的人GnRH受体的构效关系研究。GnRH II对细胞生长的抑制作用强于GnRH I。相反，GnRH I比GnRH II更能刺激促性腺激素中的信号通路--磷酸肌醇的产生。将GnRHⅡ中的不同残基(His(5)、Trp(7)、Tyr(8))单独或成对地导入GnRH I中。用His(5)取代Tyr(5)可提高GnRH I的抗增殖活性。在荷HEK293细胞株的裸鼠体内，GnRH II和拮抗剂对肿瘤生长无明显抑制作用，但D-氨基酸稳定类似物(D-Lys(6)和D-Arg(6))可抑制肿瘤生长。GnRH I和GnRH II与人GnRH受体分子模型的对接显示，GnRH I的Arg(8)与Asp(302)接触，而GnRH II的Tyr(8)似乎与不同的受体接触，这表明这些残基稳定了不同的受体构象，介导了细胞内不同的信号转导，并对促性腺激素和细胞生长产生了影响。这些发现为开发选择性促性腺激素释放激素类似物癌症治疗药物提供了基础，这些药物直接靶向肿瘤细胞或抑制垂体促性腺激素，或两者兼而有之。
GnRH and its receptor are expressed in human reproductive tract cancers, and direct antiproliferative effects of GnRH analogs have been demonstrated in cancer cell lines. The intracellular signaling responsible for this effect differs from that mediating pituitary gonadotropin secretion. The GnRH structure-activity relationship is different for the two effects. Here we report a structure-activity relationship study of GnRH agonist antiproliferative action in model cell systems of rat and human GnRH receptors stably expressed in HEK293 cells. GnRH II was more potent than GnRH I in inhibiting cell growth in the cell lines. In contrast, GnRH I was more potent than GnRH II in stimulating inositol phosphate production, the signaling pathway in gonadotropes. The different residues in GnRH II (His(5), Trp(7), Tyr(8)) were introduced singly or in pairs into GnRH I. Tyr(5) replacement by His(5) produced the highest increase in the antiproliferative potency of GnRH I. Tyr(8) substitution of Arg(8) produced the most selective analog, with very poor inositol phosphate generation but high antiproliferative potency. In nude mice bearing tumors of the HEK293 cell line, GnRH II and an antagonist administration was ineffective in inhibiting tumor growth, but D-amino acid stabilized analogs (D-Lys(6) and D-Arg(6)) ablated tumor growth. Docking of GnRH I and GnRH II to the human GnRH receptor molecular model revealed that Arg(8) of GnRH I makes contact with Asp(302), whereas Tyr(8) of GnRH II appears to make different contacts, suggesting these residues stabilize different receptor conformations mediating differential intracellular signaling and effects on gonadotropin and cell growth. These findings provide the basis for the development of selective GnRH analog cancer therapeutics that directly target tumor cells or inhibit pituitary gonadotropins or do both.