Stimulatory heterotrimeric GTP-binding protein augments cisplatin-induced apoptosis by upregulating Bak expression in human lung cancer cells
Stimulatory heterotrimeric GTP-binding protein augments cisplatin-induced apoptosis by upregulating Bak expression in human lung cancer cells
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DOI：
10.1111/j.1349-7006.2009.01136.x
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发表时间：
2009-06-01
期刊：
影响因子：
5.7
通讯作者：
Juhnn, Yong-Sung
中科院分区：
文献类型：
--
作者：
Choi, Yoon Jung;Oh, Jung-Min;Juhnn, Yong-Sung
本研究旨在探讨刺激异三聚体gtp结合（Gs）蛋白信号系统对顺铂诱导的肺癌细胞凋亡的影响及其潜在机制，以探索提高顺铂治疗效果的新策略。在A549人肺癌细胞中，G α sQL过表达增加了顺铂诱导的凋亡，用小发夹RNA敲低G α s降低了凋亡细胞的百分比。G α sQL增加了促凋亡蛋白b细胞白血病/淋巴瘤-2基因（Bcl-2）同源拮抗剂杀伤蛋白（Bak）和Bcl-2相关X蛋白（Bax）的表达，降低了抗凋亡蛋白Bcl-2和Bcl-Xlong蛋白的表达。敲除Bak可阻断G α sQL的增强作用。G α sQL降低了Bak蛋白的降解率，增加了Bak mRNA的转录水平。G α sQL以蛋白激酶a和环AMP反应元件依赖的方式增加了巴克荧光素酶活性。G α sQL还增强了顺铂诱导的缺乏功能性p53的H1299人肺癌细胞的凋亡。本研究表明，G α - s通过增加转录和降低蛋白质降解率上调Bak表达，部分增强了顺铂诱导的肺癌细胞凋亡。[j] .癌症科学2009；100:1069-1074。
The present study aimed to investigate the effect of the stimulatory heterotrimeric GTP-binding (Gs) protein signaling system on cisplatin-induced apoptosis of lung cancer cells and its underlying mechanism as an attempt to develop a novel strategy to improve the therapeutic efficacy of cisplatin. Overexpression of the constitutively active alpha subunit of Gs (G alpha sQL) in A549 human lung cancer cells increased cisplatin-induced apoptosis, and knockdown of G alpha s with small hairpin RNA decreased the percentage of apoptotic cells. G alpha sQL increased the expression of the proapoptotic proteins B-cell leukemia/lymphoma-2 genes (Bcl-2) homologous antagonist killer protein (Bak) and Bcl-2 associated X protein (Bax), and decreased the expression of the antiapoptotic proteins Bcl-2 and Bcl-Xlong protein. Knockdown of Bak blocked the augmentative effects of G alpha sQL. G alpha sQL decreased the degradation rate of the Bak protein, and increased Bak mRNA transcript levels. G alpha sQL increased Bak-luciferase activity in a protein kinase A and cyclic AMP response element-dependent manner. G alpha sQL also augmented cisplatin-induced apoptosis of H1299 human lung cancer cells that lack functional p53. From this study, it is concluded that G alpha s augments cisplatin-induced apoptosis of lung cancer cells partially through upregulating Bak expression by increasing transcription and by decreasing the rate of protein degradation. (Cancer Sci 2009; 100: 1069-1074).