Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth.
Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth.
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DOI：
10.1038/nm.2084
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发表时间：
2010-02
期刊：
影响因子：
82.9
通讯作者：
Shapiro, Steven D.
中科院分区：
文献类型：
--
作者：
Houghton, A. McGarry;Rzymkiewicz, Danuta M.;Ji, Hongbin;Gregory, Alyssa D.;Egea, Eduardo E.;Metz, Heather E.;Stolz, Donna B.;Land, Stephanie R.;Marconcini, Luiz A.;Kliment, Corrine R.;Jenkins, Kimberly M.;Beaulieu, Keith A.;Mouded, Majd;Frank, Stuart J.;Wong, Kwok K.;Shapiro, Steven D.
肺癌是全球癌症死亡的主要原因。最近的数据表明，肿瘤相关的炎症细胞可能会改变肺癌的生长和侵袭性。为了确定中性粒细胞弹性蛋白酶(NE或Elane)在肿瘤进展中的作用，我们利用小鼠肺腺癌LSL-K-ras模型建立了LSL-K-ras/Elane−/−小鼠。在诱导突变型K-ras表达后，LSL-K-ras/Elane−/−小鼠的肿瘤负荷在所有时间点均显著降低。Kaplan-Meier生存分析表明，LSL-K-ras/Elane+/+小鼠100%死亡，而缺乏NE的小鼠无一死亡。NE通过进入肿瘤细胞内的内膜室直接诱导人和小鼠肺腺癌的肿瘤细胞增殖，在那里它降解胰岛素受体底物-1(IRS1)。免疫共沉淀研究表明，随着NE降解IRS1，PI3K与强大的有丝分裂原血小板衍生生长因子受体(PDGFR)之间的相互作用增加，从而使PI3K轴向肿瘤细胞增殖倾斜。在LSL-K-ras小鼠中发现的NE和IRS1之间的反向关系在人类肺腺癌中也被发现，从而将这些发现转化为人类疾病。这项研究确定IRS1是恶性细胞内PI3K的关键调节因子。此外，这是第一次描述分泌的蛋白酶进入细胞质膜之外并改变细胞内的信号。
Lung cancer is the leading cause of cancer death worldwide. Recent data suggest that tumor-associated inflammatory cells may modify lung tumor growth and invasiveness. To determine the role of neutrophil elastase (NE or Elane) on tumor progression, we utilized the LSL-K-ras model of murine lung adenocarcinoma to generate LSL-K-ras/Elane−/− mice. Tumor burden was markedly reduced in LSL-K-ras/Elane−/− mice at all time points following induction of mutant K-ras expression. Kaplan-Meier life survival analysis demonstrated that while 100% of LSL-K-ras/Elane+/+ mice died, none of the mice lacking NE died. NE 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 (IRS1). Co-immunoprecipitation studies showed that as NE degraded IRS1, there was increased interaction between 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 NE and IRS1 in LSL-K-ras mice was also identified in human lung adenocarcinomas, thus translating these findings to human disease. This study identifies IRS1 as a key regulator of PI3K within malignant cells. Additionally, this is the first description of a secreted proteinase gaining access to a cell beyond its plasma membrane and altering intracellular signaling.
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影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
DOI：
10.1083/jcb.200409115
发表时间：
2005-05-23
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lee S;Jilani SM;Nikolova GV;Carpizo D;Iruela-Arispe ML
通讯作者：
Iruela-Arispe ML
影响因子：
11.8
作者：
Macia, Eric;Ehrlich, Marcelo;Kirchhausen, Tomas
通讯作者：
Kirchhausen, Tomas
影响因子：
8
作者：
Ji, H;Houghton, AM;Wong, KK
通讯作者：
Wong, KK
影响因子：
4.8
作者：
Rubino, M;Miaczynska, M;Zerial, M
通讯作者：
Zerial, M