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

doi:10.1038/cddis.2013.484

IOCAS-IR > 实验海洋生物学重点实验室

	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; Wang, B
	2013-12-01
发表期刊	CELL DEATH & DISEASE
ISSN	2041-4889
卷号	4 页码:e952
文章类型	Article
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.; 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.
关键词	Wentilactone a Novel Antitumor Agent Lung Cancer Ras/raf/erk/p53-p21 Pathway
学科领域	Cell Biology
DOI	10.1038/cddis.2013.484
URL	查看原文
收录类别	SCI
语种	英语
WOS研究方向	Cell Biology
WOS类目	Cell Biology
WOS记录号	WOS:000329161300013
WOS关键词	TUMOR-SUPPRESSOR PROTEIN ; CANCER-CELLS ; DNA-DAMAGE ; SIGNALING PATHWAYS ; P53 ; RAS ; DEATH ; ERK ; IDENTIFICATION ; KINASES
WOS标题词	Science & Technology ; Life Sciences & Biomedicine
引用统计	被引频次：56[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	http://ir.qdio.ac.cn/handle/337002/16676
专题	实验海洋生物学重点实验室
通讯作者	Wang, B
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..,...&Wang, 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.

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