OncoRay - National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.
J Clin Invest. 2012 Apr;122(4):1529-40. doi: 10.1172/JCI61350. Epub 2012 Mar 1.
Integrin signaling critically contributes to the progression, growth, and therapy resistance of malignant tumors. Here, we show that targeting of β₁ integrins with inhibitory antibodies enhances the sensitivity to ionizing radiation and delays the growth of human head and neck squamous cell carcinoma cell lines in 3D cell culture and in xenografted mice. Mechanistically, dephosphorylation of focal adhesion kinase (FAK) upon inhibition of β₁ integrin resulted in dissociation of a FAK/cortactin protein complex. This, in turn, downregulated JNK signaling and induced cell rounding, leading to radiosensitization. Thus, these findings suggest that robust and selective pharmacological targeting of β₁ integrins may provide therapeutic benefit to overcome tumor cell resistance to radiotherapy.
整合素信号通路对于恶性肿瘤的进展、生长和治疗抵抗至关重要。在这里，我们表明，用抑制性抗体靶向β₁整合素可提高人头颈鳞癌细胞系在 3D 细胞培养和异种移植小鼠中的电离辐射敏感性，并延缓其生长。从机制上讲，β₁整合素抑制后，粘着斑激酶（FAK）去磷酸化导致 FAK/纽蛋白蛋白复合物解离。这反过来又下调了 JNK 信号通路，诱导细胞变圆，从而导致放射增敏。因此，这些发现表明，对β₁整合素进行强有力且选择性的药理学靶向治疗可能为克服肿瘤细胞对放疗的抵抗提供治疗益处。
