Targeting the paracrine hormone-dependent guanylate cyclase/cGMP/phosphodiesterases signaling pathway for colorectal cancer prevention.
Targeting the paracrine hormone-dependent guanylate cyclase/cGMP/phosphodiesterases signaling pathway for colorectal cancer prevention.
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DOI：
10.1016/j.semcancer.2018.08.011
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发表时间：
2019-06
影响因子：
14.5
通讯作者：
N. Yarla;H. Gali;Gopal Pathuri;S. Smriti;M. Farooqui;J. Panneerselvam;G. Kumar;Venkateshwar Madka;C. Rao
中科院分区：
文献类型：
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作者：
N. Yarla;H. Gali;Gopal Pathuri;S. Smriti;M. Farooqui;J. Panneerselvam;G. Kumar;Venkateshwar Madka;C. Rao
结直肠癌（CRC）是癌症相关死亡的主要原因之一。CRC发展的风险是复杂的和多因素的，并且包括通过肿瘤抑制/促进信号通路的失调介导的肠上皮层的稳态破坏。鸟苷酸环化酶2C（GUCY 2C）是一种膜结合型鸟苷酸环化酶受体，存在于肠上皮细胞的顶膜中并维持稳态。GUCY 2C在与旁分泌激素（鸟苷素和尿鸟苷素）结合后被激活，所述旁分泌激素导致从GTP形成环GMP并激活与正常稳态相关的下游信号传导途径。GUCY 2C介导的信号传导的失调/抑制促进CRC肿瘤发生。高热量饮食诱导的肥胖与结肠上皮细胞鸟苷素表达缺乏和GUCY 2C信号沉默相关，导致肿瘤发生。因此，GUCY 2C激动剂，如利那洛肽，在预防CRC肿瘤发生中表现出相当大的作用。然而，磷酸二酯酶（PDE）在CRC肿瘤发生期间在肠上皮细胞中升高，并通过将环GMP降解为5`-GMP来阻断GUCY 2C介导的信号传导。PDE 5特异性抑制剂，如西地那非，通过放大GUCY 2C/cGMP信号通路显示出相当大的抗CRC致瘤潜力，但不能达到完全的抗致瘤作用。因此，通过向GUCY 2C提供旁分泌激素刺激和通过抑制PDE来双重靶向cGMP的升高可能是比单独更好的CRC预防策略。本文综述了GUCY 2C/cGMP/PDEs信号通路在肠上皮细胞内环境稳定中的作用。此外，还讨论了在CRC肿瘤发生过程中与该通路失调相关的事件。此外，详细描述了目前关于使用GUCY 2C激动剂和PDE抑制剂靶向GUCY 2C/cGMP/PDE通路用于CRC预防和治疗的最新进展。
Colorectal cancer (CRC) is one of the leading causes of cancer related-deaths. The risk of development of CRC is complex and multifactorial, and includes disruption of homeostasis of the intestinal epithelial layer mediated though dysregulations of tumor suppressing/promoting signaling pathways. Guanylate cyclase 2C (GUCY2C), a membrane-bound guanylate cyclase receptor, is present in the apical membranes of intestinal epithelial cells and maintains homeostasis. GUCY2C is activated upon binding of paracrine hormones (guanylin and uroguanylin) that lead to formation of cyclic GMP from GTP and activation of downstream signaling pathways that are associated with normal homeostasis. Dysregulation/suppression of the GUCY2C-mediated signaling promotes CRC tumorigenesis. High-calorie diet-induced obesity is associated with deficiency of guanylin expression and silencing ofGUCY2C-signaling in colon epithelial cells, leading to tumorigenesis. Thus, GUCY2C agonists, such as linaclotide, exhibit considerable role in preventing CRC tumorigenesis. However, phosphodiesterases (PDEs) are elevated in intestinal epithelial cells during CRC tumorigenesis and block GUCY2C-mediated signaling by degrading cyclic GMP to 5`-GMP. PDE5-specific inhibitors, such as sildenafil, show considerable anti-tumorigenic potential against CRC by amplifying the GUCY2C/cGMP signaling pathway, but cannot achieve complete anti-tumorigenic effects. Hence, dual targeting the elevation of cGMP by providing paracrine hormone stimuli to GUCY2C and by inhibition of PDEs may be a better strategy for CRC prevention than alone. This review delineates the involvement of the GUCY2C/cGMP/PDEs signaling pathway in the homeostasis of intestinal epithelial cells. Further, the events are associated with dysregulation of this pathway during CRC tumorigenesis are also discussed. In addition, current updates on targeting the GUCY2C/cGMP/PDEs pathway with GUCY2C agonists and PDEs inhibitors for CRC prevention and treatment are described in detail.