Inhibition of KRAS-dependent lung cancer cell growth by deltarasin: blockage of autophagy increases its cytotoxicity

doi:10.1038/s41419-017-0065-9

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	Inhibition of KRAS-dependent lung cancer cell growth by deltarasin: blockage of autophagy increases its cytotoxicity
	Leung, Elaine Lai Han 1,2; Luo, Lian Xiang 1; Liu, Zhong Qiu 3; Wong, Vincent Kam Wai 1; Lu, Lin Lin 3; Xie, Ying 1; Zhang, Ni 1; Qu, Yuan Qing 1; Fan, Xing Xing 1; Li, Ying 1
刊名	CELL DEATH & DISEASE
	2018-02-13
卷号	9
ISSN号	2041-4889
DOI	10.1038/s41419-017-0065-9
文献子类	Article
英文摘要	Deltarasin is a recently identified small molecule that can inhibit KRAS-PDEd interactions by binding to a hydrophobic pocket on PDEd, resulting in the impairment of cell growth, KRAS activity, and RAS/RAF signaling in human pancreatic ductal adenocarcinoma cell lines. Since KRAS mutations are the most common oncogene mutations in lung adenocarcinomas, implicated in over 30% of all lung cancer cases, we examined the ability of deltarasin to inhibit KRAS-dependent lung cancer cell growth. Here, for the first time, we document that deltarasin produces both apoptosis and autophagy in KRAS-dependent lung cancer cells in vitro and inhibits lung tumor growth in vivo. Deltarasin induces apoptosis by inhibiting the interaction of with PDEd and its downstream signaling pathways, while it induces autophagy through the AMPK-mTOR signaling pathway. Importantly, the autophagy inhibitor, 3-methyl adenine (3-MA) markedly enhances deltarasin-induced apoptosis via elevation of reactive oxygen species (ROS). In contrast, inhibition of ROS by N-acetylcysteine (NAC) significantly attenuated deltarasin-induced cell death. Collectively, these observations suggest that the anti-cancer cell activity of deltarasin can be enhanced by simultaneously blocking "tumor protective" autophagy, but inhibited if combined with an anti-oxidant.
资助项目	Macao Science and Technology Development Fund[046/2016/A2] ; Macao Science and Technology Development Fund[082/2013/A3] ; Macao Science and Technology Development Fund[086/2015/A3] ; Macao Science and Technology Development Fund[010/2016/A1] ; Macao Science and Technology Development Fund[005/2014/AMJ]
WOS关键词	PDE-DELTA ; RAS ; THERAPY ; ROS ; TRANSPORT ; DESIGN ; TUMORS ; DEATH ; DRUG ; AMPK
WOS研究方向	Cell Biology
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000427404700002
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279903]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Yao, Xiao Jun; Ward, David C.; Liu, Liang
作者单位	1.Macau Univ Sci & Technol, Macau Inst Appl Res Med & Hlth, State Key Lab Qual Res Chinese Med, Macau, Peoples R China; 2.Guangzhou Med Univ, Affiliated Hosp 1, State Key Lab Resp Dis, Guangzhou Inst Resp Dis, Guangzhou, Guangdong, Peoples R China; 3.Guangzhou Univ Chinese Med, Int Inst Translat Chinese Med, Guangzhou, Guangdong, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Leung, Elaine Lai Han,Luo, Lian Xiang,Liu, Zhong Qiu,et al. Inhibition of KRAS-dependent lung cancer cell growth by deltarasin: blockage of autophagy increases its cytotoxicity[J]. CELL DEATH & DISEASE,2018,9.
APA	Leung, Elaine Lai Han.,Luo, Lian Xiang.,Liu, Zhong Qiu.,Wong, Vincent Kam Wai.,Lu, Lin Lin.,...&Liu, Liang.(2018).Inhibition of KRAS-dependent lung cancer cell growth by deltarasin: blockage of autophagy increases its cytotoxicity.CELL DEATH & DISEASE,9.
MLA	Leung, Elaine Lai Han,et al."Inhibition of KRAS-dependent lung cancer cell growth by deltarasin: blockage of autophagy increases its cytotoxicity".CELL DEATH & DISEASE 9(2018).