Department of Thoracic/Head and Neck Medical Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA.
Cancer Biol Ther. 2009 May;8(9):801-7. doi: 10.4161/cbt.8.9.8186. Epub 2009 May 17.
Phorbol 12-myristate 13-acetate (PMA) modulates cell proliferation and survival by activating several intracellular signaling pathways. Protein kinase C (PKC) plays a key role in PMA-induced growth arrest of non-small cell lung cancer (NSCLC) cells. Kruppel-like transcription factor 6 (KLF6), which is associated with negative control of cell proliferation, is downregulated in many cancers, including NSCLC. In this study, we found that KLF6 is downregulated in 17 lung cancer cell lines and in cells representing early stages of lung cancer development. Moreover, PMA induced cell growth arrest through KLF6 induction in H358 NSCLC cells. The increase in KLF6 by PMA was associated with upregulation of the cyclin-dependent kinase inhibitors (CDKIs) p21(WAF1/CIP1) and p27(KIP1). In addition, inhibition of PKC or JNK activation decreased PMA-induced KLF6 induction and activation of PKC alone by Bryostatin-1 and Thymeleatoxin increased KLF6 levels. Moreover, siRNA-mediated knockdown of KLF6 reduced PMA-induced cell growth inhibition concomitantly with decreased expression of both p21(WAF1/CIP1) and p27(KIP1), and in accordance, overexpression of KLF6 alone upregulated both CDKIs protein levels. Our results demonstrate the induction of the tumor suppressor KLF6 following PKC activation and its importance for PMA-mediated cancer cell growth arrest.
佛波醇 12-肉豆蔻酸 13-醋酸酯（PMA）通过激活多种细胞内信号通路来调节细胞增殖和存活。蛋白激酶 C（PKC）在 PMA 诱导的非小细胞肺癌（NSCLC）细胞生长抑制中起关键作用。Kruppel 样转录因子 6（KLF6）与细胞增殖的负调控有关，在包括 NSCLC 在内的许多癌症中下调。在这项研究中，我们发现 KLF6 在 17 种肺癌细胞系和代表肺癌发展早期的细胞中下调。此外，PMA 通过诱导 H358 NSCLC 细胞中的 KLF6 诱导来诱导细胞生长停滞。PMA 引起的 KLF6 增加与细胞周期蛋白依赖性激酶抑制剂（CDKIs）p21（WAF1/CIP1）和 p27（KIP1）的上调有关。此外，抑制 PKC 或 JNK 激活可降低 PMA 诱导的 KLF6 诱导和单独用 Bryostatin-1 和 Thymeleatoxin 激活 PKC 可增加 KLF6 水平。此外，KLF6 的 siRNA 介导的敲低降低了 PMA 诱导的细胞生长抑制，同时降低了 p21（WAF1/CIP1）和 p27（KIP1）的表达，相应地，单独过表达 KLF6 可上调这两种 CDKIs 的蛋白水平。我们的结果表明，PKC 激活后诱导肿瘤抑制因子 KLF6，其对于 PMA 介导的癌细胞生长抑制很重要。
