摘要
背景:胰腺癌是癌症死亡的第四大原因,发病率上升,死亡率高。吸烟、心理应激、糖尿病、胰腺炎和酗酒是胰腺癌发生的危险因素。目的:以G蛋白偶联受体信号通路作为胰腺癌防治的靶点.方法:文献综述.结果与结论:所有已知的胰腺癌危险因素均通过肿瘤刺激Gαs-偶联β-肾上腺素和前列腺素E2受体和/或通过抑制GαI偶联GABAB受体抑制信号而引起cAMP信号传导.心理应激通过应激神经递质介导的β肾上腺素能信号的增加和GABA的抑制促进胰腺癌异种移植的进展,而应激减轻则通过逆转这些效应来抑制胰腺癌。GABA处理激活GαⅠ偶联GABAB受体信号,β阻滞剂抑制β肾上腺素能信号,环氧化酶(COX)抑制剂抑制Gαs偶联PGE 2受体信号,阻止致癌亚硝胺和转基因小鼠胰腺癌的发生和发展。心血管治疗药物(β-阻滞剂、COX-2抑制剂、Ca2-通道阻滞剂)抑制β-肾上腺素能和PGE 2信号通路用于胰腺癌干预的重新定位是有问题的,因为慢性治疗方案下存在不良的副作用。为了避免这种副作用,同时有效地减少过量的cAMP信号,应探索补充GABA或正在临床试验治疗胰腺癌成瘾的GαI-偶联受体(GABAB-Rs)的正变构调节剂(PAMs)。
关键词: 胰腺癌,G蛋白偶联受体,cAMP稳态,GαS偶联的β-肾上腺素能和PGE2受体,Gαi偶联的GABAB受体。
Current Medicinal Chemistry
Title:Regulatory Role of G Protein-coupled Receptors in Pancreatic Cancer Development and Progression
Volume: 25 Issue: 22
关键词: 胰腺癌,G蛋白偶联受体,cAMP稳态,GαS偶联的β-肾上腺素能和PGE2受体,Gαi偶联的GABAB受体。
摘要: Background: Pancreatic cancer is the fourth leading cause of cancer deaths with rising incidence and a high mortality rate. Smoking, psychological stress, diabetes, pancreatitis and alcohol abuse are known risk factors for pancreatic cancer.
Objective: Targeting G protein-coupled receptor signaling for the prevention and therapy of pancreatic cancer.
Method: Review of published literature.
Results and Conclusion: All known risk factors for pancreatic cancer cause hyperactive cyclic adenosine monophosphate (cAMP) signaling via cancer stimulating Gαs-coupled beta-adrenergic and prostaglandin E2 receptors and/or by suppressing signaling via inhibitory Gαi-coupled GABAB-receptors. Psychological stress in mice promotes the progression of pancreatic cancer xenografts via stress neurotransmitter-mediated increase in betaadrenergic signaling and suppression of GABA while stress reduction inhibits pancreatic cancer by reversing these effects. The activation of Gαi-coupled GABAB-receptor signaling by treatment with GABA, inhibition of beta-adrenergic signaling by a beta-blocker and/or suppression of Gαs-coupled PGE2 receptor signaling by a cyclooxygenase (COX) inhibitor prevent the development and progression of pancreatic cancer induced in hamsters by carcinogenic nitrosamines and in transgenic mice. The re-purposing of cardiovascular therapeutics (beta-blockers, COX-2 inhibitors, Ca2+-channel blockers) that inhibit betaadrenergic and PGE2 signaling for pancreatic cancer intervention is problematic due to undesirable side effects under chronic treatment protocols. To avoid such side effects while effectively reducing excessive cAMP signaling, nutritional GABA supplementation or positive allosteric modulators (PAMs) of Gαi-coupled receptors (GABAB-Rs) currently in clinical trials for the treatment of addiction should be explored for pancreatic cancer intervention.
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Cite this article as:
Regulatory Role of G Protein-coupled Receptors in Pancreatic Cancer Development and Progression, Current Medicinal Chemistry 2018; 25 (22) . https://dx.doi.org/10.2174/0929867324666170303121708
DOI https://dx.doi.org/10.2174/0929867324666170303121708 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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