Effects of acyclic retinoid on growth, cell cycle control, epidermal growth factor receptor signaling, and gene expression in human squamous cell carcinoma cells
Effects of acyclic retinoid on growth, cell cycle control, epidermal growth factor receptor signaling, and gene expression in human squamous cell carcinoma cells
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DOI：
10.1158/1078-0432.ccr-0714-3
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发表时间：
2004-02-01
影响因子：
11.5
通讯作者：
Weinstein, IB
中科院分区：
文献类型：
--
作者：
Shimizu, M;Suzui, M;Weinstein, IB
我们最近描述了新型化合物无环类视黄醇（ACR）在人肝癌细胞系中的生长抑制作用（M. Suzui 等人，Cancer Res.，62：3997-4006，2002）。在这项研究中，我们检查了 ACR 对人鳞状细胞癌 (SCC) 细胞的细胞和分子影响。 ACR 抑制食管 SCC 细胞系 HCE7、头颈部 SCC 细胞系 YCU-N861 和 YCU-H891 的生长，IC50 值分别与 10、25 和 40 μm 相似。然后对 HCE7 细胞进行了详细研究。用10μM ACR处理这些细胞导致GO-G细胞增加，并诱导细胞凋亡。这与分子事件的两个阶段相关。在 6-12 小时内发生的第 1 阶段，视黄酸受体 β (RARbeta) 和 p21(CIP1) 蛋白及其相应的 mRNA 增加，而视网膜母细胞瘤蛋白的过度磷酸化形式减少。在第 2 阶段（大约发生在 24 小时）期间，细胞内转化生长因子 α、磷酸化（即激活）形式的表皮生长因子受体、Stat3 和细胞外信号调节激酶蛋白的水平下降，细胞周期蛋白 D1 蛋白和 mRNA 均下降。报告基因检测表明，ACR 抑制细胞周期蛋白 D1、c-fos 和激活蛋白启动子的转录活性。另一方面，当细胞与 RARbeta 表达载体共转染时，ACR 显着刺激视黄酸反应元件-CAT 报告基因的活性。提出了解释这两个阶段的假设模型。我们通过 ACR 获得的多种效果表明，该药物可能可用于人类鳞状细胞癌的化学预防和/或治疗。
We described recently the growth inhibitory effects of the novel compound acyclic retinoid (ACR) in human hepatoma cell lines (M. Suzui et al, Cancer Res., 62: 3997-4006, 2002). In this study we examined the cellular and molecular effects of ACR on human squamous cell carcinoma (SCC) cells. ACR inhibited growth of the esophageal SCC cell line HCE7, and the head and neck SCC cell lines YCU-N861 and YCU-H891, with IC50, values of similar to10, 25, and 40 mum, respectively. Detailed studies were then done with HCE7 cells. Treatment of these cells with 10 muM ACR caused an increase of cells in GO-G, and induced apoptosis. This was associated with two phases of molecular events. During phase 1, which occurred within 6-12 h, there was an increase in the retinoic acid receptor beta (RARbeta) and p21(CIP1) proteins, and their corresponding mRNAs, and a decrease in the hyperphosphorylated form of the retinoblastoma protein. During phase 2, which occurred at similar to24 h, there was a decrease in the cellular level of transforming growth factor alpha, and the phosphorylated (i.e., activated) forms of the epidermal growth factor receptor, Stat3, and extracellular signal-regulated kinase proteins, and a decrease in both cyclin D1 protein and mRNA. Reporter assays indicated that ACR inhibited the transcriptional activity of the cyclin D1, c-fos, and activator protein promoters. On the other hand, ACR markedly stimulated the activity of a retinoic acid response element-CAT reporter when the cells were cotransfected with a RARbeta expression vector. A hypothetical model explaining these two phases is presented. The diverse effects that we obtained with ACR suggest that this agent might be useful in the chemoprevention and/or therapy of human SCCs.