OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, PF 41, 01307 Dresden, Germany.
National Center for Tumor Diseases, Partner Site Dresden: German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Cells. 2022 Jul 6;11(14):2133. doi: 10.3390/cells11142133.
Glioblastoma is a devastating malignant disease with poor patient overall survival. Strong invasiveness and resistance to radiochemotherapy have challenged the identification of molecular targets that can finally improve treatment outcomes. This study evaluates the influence of all six known p21-activated kinase (PAK) protein family members on the invasion capacity and radio-response of glioblastoma cells by employing a siRNA-based screen. In a panel of human glioblastoma cell models, we identified PAK4 as the main PAK isoform regulating invasion and clonogenic survival upon irradiation and demonstrated the radiosensitizing potential of PAK4 inhibition. Mechanistically, we show that PAK4 depletion and pharmacological inhibition enhanced the number of irradiation-induced DNA double-strand breaks and reduced the expression levels of various DNA repair proteins. In conclusion, our data suggest PAK4 as a putative target for radiosensitization and impairing DNA repair in glioblastoma, deserving further scrutiny in extended combinatorial treatment testing.
胶质母细胞瘤是一种具有较差患者总体存活率的破坏性恶性疾病。强烈的侵袭性和对放化疗的抵抗性，给能够最终改善治疗效果的分子靶标的鉴定带来了挑战。本研究通过基于 siRNA 的筛选，评估了所有六种已知的 p21 激活激酶 (PAK) 蛋白家族成员对胶质母细胞瘤细胞侵袭能力和放射反应的影响。在一组人类胶质母细胞瘤细胞模型中，我们确定 PAK4 是调节侵袭和照射后克隆存活的主要 PAK 同工型，并证明了 PAK4 抑制的放射增敏潜力。从机制上讲，我们表明 PAK4 耗竭和药理学抑制增加了照射诱导的 DNA 双链断裂的数量，并降低了各种 DNA 修复蛋白的表达水平。总之，我们的数据表明 PAK4 是胶质母细胞瘤放射增敏和削弱 DNA 修复的潜在靶点，值得在扩展的组合治疗试验中进一步研究。
