Protein Kinase Cι Drives a NOTCH3-dependent Stem-like Phenotype in Mutant KRAS Lung Adenocarcinoma

被引：94

作者：

Ali, Syed A. ^{[1
]}

Justilien, Verline ^{[1
]}

Jamieson, Lee ^{[1
]}

Murray, Nicole R. ^{[1
]}

Fields, Alan P. ^{[1
]}

机构：

[1] Mayo Clin, Ctr Canc, Dept Canc Biol, Jacksonville, FL 32224 USA

来源：

CANCER CELL | 2016年 / 29卷 / 03期

基金：

美国国家卫生研究院;

关键词：

ASYMMETRIC CELL-DIVISION; SMALL-MOLECULE INHIBITOR; TRANSFORMED GROWTH; PHASE-I; CANCER GENOMICS; COMPLEX; PATHWAY; AUROTHIOMALATE; ACTIVATION; IDENTIFICATION;

D O I：

10.1016/j.ccell.2016.02.012

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

We report that the protein kinase C iota (PKC iota) oncogene controls expression of NOTCH3, a key driver of stemness, in KRAS-mediated lung adenocarcinoma (LADC). PKC iota activates NOTCH3 expression by phosphorylating the ELF3 transcription factor and driving ELF3 occupancy on the NOTCH3 promoter. PKC iota-ELF3-NOTCH3 signaling controls the tumor-initiating cell phenotype by regulating asymmetric cell division, a process necessary for tumor initiation and maintenance. Primary LADC tumors exhibit PKC iota-ELF3-NOTCH3 signaling, and combined pharmacologic blockade of PKC iota and NOTCH synergistically inhibits tumorigenic behavior in vitro and LADC growth in vivo demonstrating the therapeutic potential of PKC iota-ELF3-NOTCH3 signal inhibition to more effectively treat KRAS LADC.

引用

页码：367 / 378

页数：12

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