Teferi Nahom, Ekanayake Akalanka, Owusu Stephenson B, Moninger Thomas O, Sarkaria Jann N, Tivanski Alexei V, Petronek Michael S
Department of Neurosurgery, University of Iowa, Iowa City, IA, USA.
Department of Chemistry, University of Iowa, Iowa City, IA, USA.
J Biol Eng. 2024 Dec 21;18(1):72. doi: 10.1186/s13036-024-00472-x.
Glioblastoma tumors are the most common and aggressive adult central nervous system malignancy. Nearly all patients experience disease progression, which significantly contributes to disease mortality. Recently, it has been suggested that recurrent tumors may be characterized by a ferroptosis-prone phenotype with a significant decrease in glutathione peroxidase 4 (GPx4) expression. This led to the hypothesis that GPx4 expression negatively influences GBM cell growth. This study utilizes a doxycycline inducible GPx4 overexpression model to test this hypothesis. Consistently, the overexpression of GPx4 significantly impairs cell growth and colony formation while also causing an accumulation of cells in G1/G0 phase of the cell cycle. From a biophysical perspective, GPx4 overexpressing cells have significantly greater surface area, increased Young's modulus, and experience anomalous sub-diffusion as opposed to normal diffusion associated with Brownian motion. Moreover, analysis of patient derived GBM cells reveal that cell growth rates, plating efficiency, and Young's modulus are all inversely proportional to GPx4 expression. Therefore, GPx4 appears to be a biophysical regulator of GBM cell growth that warrants further mechanistic investigation in its role in GBM progression.
胶质母细胞瘤是成人中枢神经系统中最常见且侵袭性最强的恶性肿瘤。几乎所有患者都会经历疾病进展，这在很大程度上导致了疾病死亡率。最近，有人提出复发性肿瘤可能具有易于发生铁死亡的表型，谷胱甘肽过氧化物酶4（GPx4）表达显著降低。这引发了一个假设，即GPx4表达对胶质母细胞瘤细胞生长具有负面影响。本研究利用强力霉素诱导的GPx4过表达模型来验证这一假设。一致的是，GPx4的过表达显著损害细胞生长和集落形成，同时还导致细胞在细胞周期的G1/G0期积累。从生物物理学角度来看，与布朗运动相关的正常扩散相反，过表达GPx4的细胞具有显著更大的表面积、增加的杨氏模量，并经历异常的亚扩散。此外，对源自患者的胶质母细胞瘤细胞的分析表明，细胞生长速率、接种效率和杨氏模量均与GPx4表达呈反比。因此，GPx4似乎是胶质母细胞瘤细胞生长的生物物理调节因子，其在胶质母细胞瘤进展中的作用值得进一步进行机制研究。
