Proteins kinase Cε is required for non-small cell lung carcinoma growth and regulates the expression of apoptotic genes
Proteins kinase Cε is required for non-small cell lung carcinoma growth and regulates the expression of apoptotic genes
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DOI：
10.1038/onc.2011.428
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发表时间：
2012-05-01
期刊：
影响因子：
8
通讯作者：
Kazanietz, M. G.
中科院分区：
文献类型：
--
作者：
Caino, M. C.;Lopez-Haber, C.;Kazanietz, M. G.
蛋白激酶C (PKC)epsilon是新PKC家族的成员，在正常细胞和癌细胞的有丝分裂和存活中起关键作用。PKC epsilon在上皮性癌症中经常过表达，尤其是在肺癌中。使用短发夹RNA方法，我们在这里确定PKCe是体外非小细胞肺癌（NSCLC）生长以及接种到胸腺小鼠体内肿瘤生长所必需的。此外，持续递送PKC epsilon选择性抑制剂肽（epsilon V1-2）可降低小鼠异种移植物的生长。RNA干扰去除和PKCe的药理抑制均可导致NSCLC肿瘤中凋亡细胞数量的显著增加。PKC epsilon缺失的NSCLC细胞显示Bcl2家族促凋亡蛋白、caspase募集结构域蛋白和肿瘤坏死因子配体/受体超家族成员的表达升高。此外，基因集富集分析显示，在PKC epsilon缺失细胞中发生改变的绝大多数基因在人类NSCLC中也不受调控。我们的研究结果强烈提示PKC epsilon是NSCLC细胞存活和维持NSCLC肿瘤生长所必需的。因此，PKC epsilon可能是一个有吸引力的非小细胞肺癌治疗靶点。中华肿瘤杂志，2012,31 (3):593- 596；doi: 10.1038 / onc.2011.428;2011年9月26日在线发布
Protein kinase C (PKC)epsilon, a member of the novel PKC family, has key roles in mitogenesis and survival in normal and cancer cells. PKC epsilon is frequently overexpressed in epithelial cancers, particularly in lung cancer. Using a short-hairpin RNA approach, here we established that PKCe is required for non-small cell lung carcinoma (NSCLC) growth in vitro as well as tumor growth when inoculated into athymic mice. Moreover, sustained delivery of a PKC epsilon-selective inhibitor peptide, epsilon V1-2, reduced xenograft growth in mice. Both RNA interference depletion and pharmacological inhibition of PKCe caused a marked elevation in the number of apoptotic cells in NSCLC tumors. PKC epsilon-depleted NSCLC cells show elevated expression of pro-apoptotic proteins of the Bcl2 family, caspase recruitment domain-containing proteins and tumor necrosis factor ligands/receptor superfamily members. Moreover, a Gene Set Enrichment Analysis revealed that a vast majority of the genes changed in PKC epsilon-depleted cells were also deregulated in human NSCLC. Our results strongly suggest that PKC epsilon is required for NSCLC cell survival and maintenance of NSCLC tumor growth. Therefore, PKC epsilon may represent an attractive therapeutic target for NSCLC. Oncogene (2012) 31, 2593-2600; doi:10.1038/onc.2011.428; published online 26 September 2011