Natriuretic peptide receptor A inhibition suppresses gastric cancer development through reactive oxygen species-mediated G2/M cell cycle arrest and cell death
Natriuretic peptide receptor A inhibition suppresses gastric cancer development through reactive oxygen species-mediated G2/M cell cycle arrest and cell death
复制标题
DOI：
10.1016/j.freeradbiomed.2016.08.019
复制
发表时间：
2016-10-01
影响因子：
7.4
通讯作者：
Xu, Ze-Kuan
中科院分区：
文献类型：
--
作者：
Li, Zheng;Wang, Ji-Wei;Xu, Ze-Kuan
心房利钠肽受体A（NPRA）是心房利钠肽（ANP）的主要受体，与肿瘤的发生有关，但ANP-NPRA信号通路在胃癌发生中的作用尚不清楚。免疫组化分析显示NPRA表达与胃癌的大小和分期呈正相关。通过shRNA抑制NPRA可诱导胃癌细胞G2/M期细胞周期阻滞、细胞死亡和自噬，这是由于活性氧（ROS）的积累。自噬的遗传或药物抑制导致半胱天冬酶依赖性细胞死亡。因此，NPRA沉默诱导的自噬可能代表了一种细胞保护机制。ROS积累激活c-Jun N-末端激酶（JNK）和AMP-活化蛋白激酶（AMPK）。ROS介导的JNK激活通过干扰细胞周期和降低细胞活力来抑制细胞增殖。此外，AMPK激活促进NPRA下调的癌细胞中的自噬。总之，我们的研究结果表明，抑制NPRA抑制胃癌的发展和针对NPRA可能是一个有前途的策略，用于治疗胃癌。(C)2016 Elsevier Inc. All rights reserved.
Natriuretic peptide receptor A (NPRA), the major receptor for atrial natriuretic peptide (ANP), has been implicated in tumorigenesis; however, the role of ANP-NPRA signaling in the development of gastric cancer remains unclear. Immunohistochemical analyses indicated that NPRA expression was positively associated with gastric tumor size and cancer stage. NPRA inhibition by shRNA induced G2/M cell cycle arrest, cell death, and autophagy in gastric cancer cells, due to accumulation of reactive oxygen species (ROS). Either genetic or pharmacologic inhibition of autophagy led to caspase-dependent cell death. Therefore, autophagy induced by NPRA silencing may represent a cytoprotective mechanism. ROS accumulation activated c-Jun N-terminal kinase (JNK) and AMP-activated protein kinase (AMPK). ROSmediated activation of JNK inhibited cell proliferation by disturbing cell cycle and decreased cell viability. In addition, AMPK activation promoted autophagy in NPRA-downregulated cancer cells. Overall, our results indicate that the inhibition of NPRA suppresses gastric cancer development and targeting NPRA may represent a promising strategy for the treatment of gastric cancer. (C) 2016 Elsevier Inc. All rights reserved.