Brkic Faris F, Stoiber Stefan, Maier Tobias, Gurnhofer Elisabeth, Kenner Lukas, Heiduschka Gregor, Kadletz-Wanke Lorenz
Department of Otorhinolaryngology and Head and Neck Surgery, Medical University of Vienna, 1090 Vienna, Austria.
Department of Pathology, Medical University of Vienna, 1090 Vienna, Austria.
Pharmaceuticals (Basel). 2022 Mar 20;15(3):378. doi: 10.3390/ph15030378.
Wnt/Beta-Catenin signaling is involved in the carcinogenesis of different solid malignant tumors. The interaction of Creb-binding protein (CBP) with Beta-Catenin is a pivotal component of the Wnt/Beta-Catenin signaling pathway. The first aim of this study was to evaluate the association of CBP expression with survival in patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC). Second, the in vitro effects of the inhibition of CBP/Beta-Catenin interaction were analyzed. In particular, the effects of ICG-001, an inhibitor of CBP/Beta-Catenin interaction, on proliferation, cell death, modulation of Wnt/Beta-Catenin target expression, and cell migration were examined in vitro. High CBP expression is significantly associated with better survival on mRNA and protein levels. Furthermore, we observed cytotoxic as well as anti-migratory effects of ICG-001. These effects were particularly more potent in the HPV-positive than in the -negative cell line. Mechanistically, ICG-001 treatment induced apoptosis and led to a downregulation of CBP, c-MYC, and Cyclin D1 in HPV-positive cells, indicating inhibition of Wnt/Beta-Catenin signaling. In conclusion, high CBP expression is observed in HPV-positive HNSCC patients with a good prognosis, and ICG-001 showed a promising antineoplastic potential, particularly in HPV-positive HNSCC cells. Therefore, ICG-001 may potentially become an essential component of treatment de-escalation regimens for HPV-positive HNSCC. Further studies are warranted for additional assessment of the mechanistic background of our in vitro findings.
Wnt/β-连环蛋白信号通路参与不同实体恶性肿瘤的致癌过程。Creb结合蛋白（CBP）与β-连环蛋白的相互作用是Wnt/β-连环蛋白信号通路的关键组成部分。本研究的首要目的是评估CBP表达与人类乳头瘤病毒（HPV）阳性头颈部鳞状细胞癌（HNSCC）患者生存的相关性。其次，分析了抑制CBP/β-连环蛋白相互作用的体外效应。特别地，在体外研究了CBP/β-连环蛋白相互作用抑制剂ICG-001对增殖、细胞死亡、Wnt/β-连环蛋白靶标表达调节及细胞迁移的影响。在mRNA和蛋白质水平上，高CBP表达与更好的生存显著相关。此外，我们观察到了ICG-001的细胞毒性和抗迁移效应。这些效应在HPV阳性细胞系中比在HPV阴性细胞系中更为显著。从机制上讲，ICG-001处理诱导了HPV阳性细胞的凋亡，并导致CBP、c-MYC和细胞周期蛋白D1的下调，表明Wnt/β-连环蛋白信号通路受到抑制。总之，在预后良好的HPV阳性HNSCC患者中观察到高CBP表达，且ICG-001显示出有前景的抗肿瘤潜力，尤其是在HPV阳性HNSCC细胞中。因此，ICG-001可能会成为HPV阳性HNSCC治疗降阶梯方案的重要组成部分。有必要进行进一步研究以对我们体外研究结果的机制背景进行额外评估。
