Wentilactone A as a novel potential antitumor agent induces apoptosis and G2/M arrest of human lung carcinoma cells, and is mediated by HRas-GTP accumulation to excessively activate the Ras/Raf/ERK/p53-p21 pathway

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	Wentilactone A as a novel potential antitumor agent induces apoptosis and G2/M arrest of human lung carcinoma cells, and is mediated by HRas-GTP accumulation to excessively activate the Ras/Raf/ERK/p53-p21 pathway
	Lv, C.1; Hong, Y.2; Miao, L.3,4; Li, C.5 ; Xu, G.5; Wei, S.1; Wang, B.5; Huang, C.1 ; Jiao, B.1
刊名	CELL DEATH & DISEASE
	2013-12-01
卷号	4 页码:e952
关键词	Wentilactone A novel antitumor agent lung cancer Ras/Raf/ERK/p53-p21 pathway
ISSN号	2041-4889
通讯作者	Wang, B
中文摘要	Chemotherapy remains the common therapeutic for patients with lung cancer. Novel, selective antitumor agents are pressingly needed. This study is the first to investigate a different, however, effective antitumor drug candidate Wentilactone A (WA) for its development as a novel agent. In NCI-H460 and NCI-H446 cell lines, WA triggered G2/M phase arrest and mitochondrial-related apoptosis, accompanying the accumulation of reactive oxygen species (ROS). It also induced activation of mitogen-activated protein kinase and p53 and increased expression of p21. When we pre-treated cells with ERK, JNK, p38, p53 inhibitor or NAC followed by WA treatment, only ERK and p53 inhibitors blocked WA-induced apoptosis and G2/M arrest. We further observed Ras (HRas, KRas and NRas) and Rat activation, and found that WA treatment increased HRas Raf activation. Knockdown of HRas by using small interfering RNA (siRNA) abolished WA-induced apoptosis and G2/M arrest. HRas siRNA also halted Raf, ERK, p53 activation and p21 accumulation. Molecular docking analysis suggested that WA could bind to HRas-GTP, causing accumulation of Ras-GTP and excessive activation of RaVERK/p53-p21. The direct binding affinity was confirmed by surface plasmon resonance (SPR). In vivo, WA suppressed tumor growth without adverse toxicity and presented the same mechanism as that in vitro. Taken together, these findings suggest WA as a promising novel, potent and selective antitumor drug candidate for lung cancer.
英文摘要	Chemotherapy remains the common therapeutic for patients with lung cancer. Novel, selective antitumor agents are pressingly needed. This study is the first to investigate a different, however, effective antitumor drug candidate Wentilactone A (WA) for its development as a novel agent. In NCI-H460 and NCI-H446 cell lines, WA triggered G2/M phase arrest and mitochondrial-related apoptosis, accompanying the accumulation of reactive oxygen species (ROS). It also induced activation of mitogen-activated protein kinase and p53 and increased expression of p21. When we pre-treated cells with ERK, JNK, p38, p53 inhibitor or NAC followed by WA treatment, only ERK and p53 inhibitors blocked WA-induced apoptosis and G2/M arrest. We further observed Ras (HRas, KRas and NRas) and Rat activation, and found that WA treatment increased HRas Raf activation. Knockdown of HRas by using small interfering RNA (siRNA) abolished WA-induced apoptosis and G2/M arrest. HRas siRNA also halted Raf, ERK, p53 activation and p21 accumulation. Molecular docking analysis suggested that WA could bind to HRas-GTP, causing accumulation of Ras-GTP and excessive activation of RaVERK/p53-p21. The direct binding affinity was confirmed by surface plasmon resonance (SPR). In vivo, WA suppressed tumor growth without adverse toxicity and presented the same mechanism as that in vitro. Taken together, these findings suggest WA as a promising novel, potent and selective antitumor drug candidate for lung cancer.
学科主题	Cell Biology
WOS标题词	Science & Technology ; Life Sciences & Biomedicine
类目[WOS]	Cell Biology
研究领域[WOS]	Cell Biology
关键词[WOS]	TUMOR-SUPPRESSOR PROTEIN ; CANCER-CELLS ; DNA-DAMAGE ; SIGNALING PATHWAYS ; P53 ; RAS ; DEATH ; ERK ; IDENTIFICATION ; KINASES
收录类别	SCI
原文出处	10.1038/cddis.2013.484
语种	英语
WOS记录号	WOS:000329161300013
公开日期	2014-07-17
内容类型	期刊论文
源URL	[http://ir.qdio.ac.cn/handle/337002/16676]
专题	海洋研究所_实验海洋生物学重点实验室
作者单位	1.Second Mil Med Univ, Dept Biochem & Mol Biol, Shanghai 200433, Peoples R China 2.Zhejiang Chinese Med Univ, Coll Pharmaceut Sci, Teaching & Res Off Chinese Mat Med, Hangzhou 310052, Zhejiang, Peoples R China 3.Fudan Univ, Dept Pharmacol, Sch Pharm, Shanghai 200032, Peoples R China 4.Fudan Univ, Inst Biomed Sci, Shanghai 200032, Peoples R China 5.Chinese Acad Sci, Inst Oceanol, Key Lab Expt Marine Biol, Qingdao 266071, Peoples R China
推荐引用方式 GB/T 7714	Lv, C.,Hong, Y.,Miao, L.,et al. Wentilactone A as a novel potential antitumor agent induces apoptosis and G2/M arrest of human lung carcinoma cells, and is mediated by HRas-GTP accumulation to excessively activate the Ras/Raf/ERK/p53-p21 pathway[J]. CELL DEATH & DISEASE,2013,4:e952.
APA	Lv, C..,Hong, Y..,Miao, L..,Li, C..,Xu, G..,...&Jiao, B..(2013).Wentilactone A as a novel potential antitumor agent induces apoptosis and G2/M arrest of human lung carcinoma cells, and is mediated by HRas-GTP accumulation to excessively activate the Ras/Raf/ERK/p53-p21 pathway.CELL DEATH & DISEASE,4,e952.
MLA	Lv, C.,et al."Wentilactone A as a novel potential antitumor agent induces apoptosis and G2/M arrest of human lung carcinoma cells, and is mediated by HRas-GTP accumulation to excessively activate the Ras/Raf/ERK/p53-p21 pathway".CELL DEATH & DISEASE 4(2013):e952.