Muñoz-Moreno Laura, Román Irene D, Bajo Ana M
Departamento de Biología de Sistemas. Unidad de Bioquímica y Biología Molecular (Research group "Cánceres de origen epitelial"), Universidad de Alcalá, Campus Científico-Tecnológico, 28871, Alcalá de Henares, Madrid, Spain.
Rev Endocr Metab Disord. 2024 Nov 7. doi: 10.1007/s11154-024-09922-9.
In the late 1960s and early 1970s, hypothalamic regulatory hormones were isolated, characterized and sequenced. Later, it was demonstrated hypothalamic and ectopic production of growth hormone-releasing hormone (GHRH) in normal and tumor tissues, of both humans and animals. Pituitary-type GHRH receptors (pGHRH-R) had been demonstrated to be expressed predominantly in the anterior pituitary gland but also found in other somatic cells, and significantly present in various human cancers; in addition, the expression of splice variants (SVs) of GHRH receptor (GHRH-R) has been found not only in the pituitary but in extrapituitary tissues, including human neoplasms. In relation to the prostate, besides the pGHRH-R, it has been detected the presence of truncated splice variants of GHRH-R (SV1-SV4) in normal human prostate and human prostate cancer (PCa) specimens; lastly, a novel SV of GHRH-R has been detected in human PCa. Signaling pathways activated by GHRH include AC/cAMP/PKA, Ras/Raf/ERK, PI3K/Akt/mTOR and JAK2/STAT3, which are involved in processes such as cell survival, proliferation and cytokine secretion. The neuropeptide GHRH can also transactivate the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER)-2. Thus, GHRH-Rs have become drug targets for several types of clinical conditions, including prostate-related conditions such as prostatitis, benign hyperplasia and cancer. Over the last fifty years, the development of GHRH-R receptor antagonists has been unstoppable, improving their potency, stability and affinity for the receptor. The last series of GHRH-R antagonists, AVR, exhibits superior anticancer and anti-inflammatory activities in both in vivo and in vitro assays.
在20世纪60年代末和70年代初，下丘脑调节激素被分离、鉴定并测序。后来，在人和动物的正常及肿瘤组织中均证实了生长激素释放激素（GHRH）的下丘脑和异位产生。垂体型GHRH受体（pGHRH-R）已被证明主要在前垂体中表达，但也存在于其他体细胞中，并且在各种人类癌症中大量存在；此外，GHRH受体（GHRH-R）剪接变体（SVs）不仅在垂体中，而且在包括人类肿瘤在内的垂体外组织中也有发现。关于前列腺，除了pGHRH-R外，在正常人前列腺和人类前列腺癌（PCa）标本中还检测到了GHRH-R的截短剪接变体（SV1-SV4）；最后，在人类PCa中检测到了一种新型的GHRH-R SV。GHRH激活的信号通路包括AC/cAMP/PKA、Ras/Raf/ERK、PI3K/Akt/mTOR和JAK2/STAT3，这些通路参与细胞存活、增殖和细胞因子分泌等过程。神经肽GHRH还可以反式激活表皮生长因子受体（EGFR）和人表皮生长因子受体（HER）-2。因此，GHRH-Rs已成为几种临床病症的药物靶点，包括与前列腺相关的病症，如前列腺炎、良性增生和癌症。在过去的五十年里，GHRH-R受体拮抗剂的开发势不可挡，其效力、稳定性和对受体的亲和力不断提高。最新系列的GHRH-R拮抗剂AVR在体内和体外试验中均表现出卓越的抗癌和抗炎活性。
