Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth

	Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth
	Houghton, AM; Rzymkiewicz, DM; Ji, HB; Gregory, AD; Egea, EE; Metz, HE; Stolz, DB; Land, SR; Marconcini, LA; Kliment, CR
刊名	NATURE MEDICINE
	2010
卷号	16 期号:2 页码:219-U127
通讯作者	Houghton, AM (reprint author), Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15260 USA.,houghtonm@dom.pitt.edu
英文摘要	Lung cancer is the leading cause of cancer death worldwide(1). Recent data suggest that tumor-associated inflammatory cells may modify lung tumor growth and invasiveness(2,3). To determine the role of neutrophil elastase (encoded by Elane) on tumor progression, we used the loxP-Stop-loxP K-ras(G12D) (LSL-K-ras) model of mouse lung adenocarcinoma(4) to generate LSL-K-ras-Elane(-/-) mice. Tumor burden was markedly reduced in LSL-K-ras-Elane(-/-) mice at all time points after induction of mutant K-ras expression. Kaplan-Meier survival analysis showed that whereas all LSL-K-ras-Elane(+/+) mice died, none of the mice lacking neutrophil elastase died. Neutrophil elastase directly induced tumor cell proliferation in both human and mouse lung adenocarcinomas by gaining access to an endosomal compartment within tumor cells, where it degraded insulin receptor substrate-1 (IRS-1). Immunoprecipitation studies showed that, as neutrophil elastase degraded IRS-1, there was increased interaction between phosphatidylinositol 3-kinase (PI3K) and the potent mitogen platelet-derived growth factor receptor (PDGFR), thereby skewing the PI3K axis toward tumor cell proliferation. The inverse relationship identified between neutrophil elastase and IRS-1 in LSL-K-ras mice was also identified in human lung adenocarcinomas, thus translating these findings to human disease. This study identifies IRS-1 as a key regulator of PI3K within malignant cells. Additionally, to our knowledge, this is the first description of a secreted proteinase gaining access to the inside of a cell and altering intracellular signaling.
学科主题	Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine
类目[WOS]	Biochemistry & Molecular Biology ; Cell Biology ; Medicine, Research & Experimental
关键词[WOS]	INSULIN-RECEPTOR SUBSTRATE-1 ; LEUKOCYTE ELASTASE ; G972R VARIANT ; K-RAS ; CANCER ; INTERLEUKIN-8 ; ASSOCIATION ; EXPRESSION ; PHOSPHORYLATION ; INFLAMMATION
收录类别	SCI
语种	英语
WOS记录号	WOS:000274297000044
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/961]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Houghton, AM,Rzymkiewicz, DM,Ji, HB,et al. Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth[J]. NATURE MEDICINE,2010,16(2):219-U127.
APA	Houghton, AM.,Rzymkiewicz, DM.,Ji, HB.,Gregory, AD.,Egea, EE.,...&Shapiro, SD.(2010).Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth.NATURE MEDICINE,16(2),219-U127.
MLA	Houghton, AM,et al."Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth".NATURE MEDICINE 16.2(2010):219-U127.