Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Oncogene. 2012 May 17;31(20):2593-600. doi: 10.1038/onc.2011.428. Epub 2011 Sep 26.
Protein kinase C (PKC)ɛ, a member of the novel PKC family, has key roles in mitogenesis and survival in normal and cancer cells. PKCɛ is frequently overexpressed in epithelial cancers, particularly in lung cancer. Using a short-hairpin RNA approach, here we established that PKCɛ 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 PKCɛ-selective inhibitor peptide, ɛV1-2, reduced xenograft growth in mice. Both RNA interference depletion and pharmacological inhibition of PKCɛ caused a marked elevation in the number of apoptotic cells in NSCLC tumors. PKCɛ-depleted NSCLC cells show elevated expression of pro-apoptotic proteins of the Bcl-2 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 PKCɛ-depleted cells were also deregulated in human NSCLC. Our results strongly suggest that PKCɛ is required for NSCLC cell survival and maintenance of NSCLC tumor growth. Therefore, PKCɛ may represent an attractive therapeutic target for NSCLC.
蛋白激酶 C（PKC）ɛ，新型 PKC 家族的一员，在正常和癌细胞的有丝分裂和存活中发挥关键作用。PKCɛ 在上皮性癌中频繁过表达，尤其是在肺癌中。通过短发夹 RNA 方法，我们在这里证实 PKCɛ 对于非小细胞肺癌（NSCLC）体外生长以及接种到无胸腺小鼠中的肿瘤生长是必需的。此外，PKCɛ 选择性抑制剂肽 ɛV1-2 的持续递送可减少小鼠异种移植物的生长。RNA 干扰耗竭和 PKCɛ 的药理学抑制均可导致 NSCLC 肿瘤中凋亡细胞数量的显著增加。PKCɛ 耗竭的 NSCLC 细胞显示出 Bcl-2 家族、半胱天冬酶募集域蛋白和肿瘤坏死因子配体/受体超家族成员的促凋亡蛋白的表达升高。此外，基因集富集分析表明，在 PKCɛ 耗竭细胞中改变的绝大多数基因在人类 NSCLC 中也失调。我们的研究结果强烈表明 PKCɛ 对于 NSCLC 细胞存活和 NSCLC 肿瘤生长的维持是必需的。因此，PKCɛ 可能是 NSCLC 的一个有吸引力的治疗靶点。
