The peptide mimetic, NC114, is a promising anticancer compound that specifically kills colorectal cancer cells without affecting normal colon epithelial cells. In our previous study, we observed that NC114 inhibited the Wnt/β-catenin pathway, with significant downregulation of both Ser 675-phosphorylated β-catenin and its target genes, cyclin D1 and survivin. However, the molecular mechanism responsible for its cytotoxic effect has not yet been fully characterized. In the present study, we demonstrated that NC114 prevented cell cycle progression from S to G2/M phase by downregulating cell cycle-related gene expression, and also induced growth arrest in SW480 and HCT-116 colorectal cancer cells. A novel covariation network analysis combined with transcriptome analysis revealed a series of signaling cascades affected by NC114 treatment, and identified protein kinase C-δ (PKCδ) and forkhead box protein M1 (FOXM1) as important regulatory factors for NC114-induced growth arrest. NC114 treatment inhibits the activation of PKCδ and its kinase activity, which suppresses MEK/ERK signaling. Attenuated MEK/ERK signaling then results in a reduction in FOXM1 phosphorylation and subsequent nuclear translocation of FOXM1 and β-catenin. Consequently, formation of a T-cell factor-4 (TCF4)/β-catenin transcription complex in the nucleus is inhibited and transcription of its target genes, such as cell cycle-related genes, is downregulated. The efficacy of NC114 on tumor growth was confirmed in a xenograft model. Collectively, elucidation of the mechanism by which NC114 induces growth arrest in colorectal cancer cells should provide a novel therapeutic strategy for colorectal cancer treatment.

中文翻译：

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肽模拟物 NC114 通过阻止结直肠癌细胞中 PKCδ 激活和 FOXM1 核转位来诱导生长停滞

肽模拟物 NC114 是一种有前途的抗癌化合物，可以特异性杀死结直肠癌细胞，而不影响正常结肠上皮细胞。在我们之前的研究中，我们观察到 NC114 抑制 Wnt/β-catenin 通路，并显着下调 Ser 675 磷酸化 β-catenin 及其靶基因 cyclin D1 和 survivin。然而，其细胞毒性作用的分子机制尚未完全阐明。在本研究中，我们证明NC114通过下调细胞周期相关基因的表达来阻止细胞周期从S期进展到G2/M期，并且还诱导SW480和HCT-116结直肠癌细胞的生长停滞。新颖的共变网络分析与转录组分析相结合，揭示了一系列受 NC114 处理影响的信号级联反应，并确定蛋白激酶 C-δ (PKCδ) 和叉头盒蛋白 M1 (FOXM1) 是 NC114 诱导的生长停滞的重要调节因子。 NC114 治疗可抑制 PKCδ 的激活及其激酶活性，从而抑制 MEK/ERK 信号传导。 MEK/ERK 信号传导减弱会导致 FOXM1 磷酸化减少以及随后 FOXM1 和 β-连环蛋白的核转位。因此，细胞核中 T 细胞因子 4 (TCF4)/β-连环蛋白转录复合物的形成受到抑制，其靶基因（例如细胞周期相关基因）的转录被下调。 NC114 对肿瘤生长的功效在异种移植模型中得到证实。总的来说，阐明 NC114 诱导结直肠癌细胞生长停滞的机制应该为结直肠癌的治疗提供一种新的治疗策略。