Protein Kinase Cι Drives a NOTCH3-dependent Stem-like Phenotype in Mutant KRAS Lung Adenocarcinoma.
Protein Kinase Cι Drives a NOTCH3-dependent Stem-like Phenotype in Mutant KRAS Lung Adenocarcinoma.
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DOI：
10.1016/j.ccell.2016.02.012
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发表时间：
2016-03-14
期刊：
影响因子：
50.3
通讯作者：
Fields AP
中科院分区：
文献类型：
--
作者：
Ali SA;Justilien V;Jamieson L;Murray NR;Fields AP
我们报道了蛋白激酶C i（PKC i）癌基因控制KRAS介导的肺腺癌（LADC）中NOTCH 3的表达，NOTCH 3是干性的关键驱动因素。PKC 1通过磷酸化ELF 3转录因子并驱动ELF 3占据N 0 TCH 3启动子来激活N 0 TCH 3表达。PKC 1-ELF 3-N 0 TCH 3信号传导通过调节不对称细胞分裂（肿瘤起始和维持所必需的过程）来控制肿瘤起始细胞（TIC）表型。原发性LADC肿瘤表现出PKC 1-ELF 3-N 0 TCH 3信号传导，并且PKC 1和N 0 TCH的组合药理学阻断协同抑制体外致瘤行为和体内LADC生长，证明了PKC 1-ELF 3-N 0 TCH 3信号抑制更有效地治疗KRAS LADC的治疗潜力。Ali等人显示，在KRAS介导的肺腺癌中，PKC 1通过使ELF 3磷酸化并驱动在N 0 TCH 3启动子处的占据来控制N 0 TCH 3表达。PKC 1-ELF 3-NOTCH 3信号传导控制TIC表型，并且PKC 1和NOTCH的组合阻断在体外和体内具有协同抗肿瘤作用。
We report that the protein kinase Cι (PKCι) oncogene controls expression of NOTCH3, a key driver of stemness, in KRAS-mediated lung adenocarcinoma (LADC). PKCι activates NOTCH3 expression by phosphorylating the ELF3 transcription factor and driving ELF3 occupancy on the NOTCH3 promoter. PKCι-ELF3-NOTCH3 signaling controls the tumor-initiating cell (TIC) phenotype by regulating asymmetric cell division, a process necessary for tumor initiation and maintenance. Primary LADC tumors exhibit PKCι-ELF3-NOTCH3 signaling, and combined pharmacologic blockade of PKCι and NOTCH synergistically inhibits tumorigenic behavior in vitro and LADC growth in vivo demonstrating the therapeutic potential of PKCι-ELF3-NOTCH3 signal inhibition to more effectively treat KRAS LADC. Ali et al. show that in KRAS-mediated lung adenocarcinoma, PKCι controls NOTCH3 expression by phosphorylating ELF3 and driving occupancy at the NOTCH3 promoter. PKCι-ELF3-NOTCH3 signaling controls the TIC phenotype and combined blockade of PKCι and NOTCH has a synergistic anti-tumor effect in vitro and in vivo.