Instituto de Neurociencias de Castilla y León (INCYL), Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Calle Pintor Fernando Gallego 1, Salamanca, 37007, Spain.
Instituto de Neurociencias de Castilla y León (INCYL), Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Calle Pintor Fernando Gallego 1, Salamanca, 37007, Spain.
Transl Res. 2024 Oct;272:95-110. doi: 10.1016/j.trsl.2024.06.001. Epub 2024 Jun 12.
Glioblastoma (GBM) is the most frequent and aggressive primary brain cancer. The Src inhibitor, TAT-Cx43, exerts antitumor effects in in vitro and in vivo models of GBM. Because addressing the mechanism of action is essential to translate these results to a clinical setting, in this study we carried out an unbiased proteomic approach. Data-independent acquisition mass spectrometry proteomics allowed the identification of 190 proteins whose abundance was modified by TAT-Cx43. Our results were consistent with the inhibition of Src as the mechanism of action of TAT-Cx43 and unveiled antitumor effectors, such as p120 catenin. Changes in the abundance of several proteins suggested that TAT-Cx43 may also impact the brain microenvironment. Importantly, the proteins whose abundance was reduced by TAT-Cx43 correlated with an improved GBM patient survival in clinical datasets and none of the proteins whose abundance was increased by TAT-Cx43 correlated with shorter survival, supporting its use in clinical trials.
胶质母细胞瘤（GBM）是最常见和侵袭性最强的原发性脑癌。Src 抑制剂 TAT-Cx43 在 GBM 的体外和体内模型中发挥抗肿瘤作用。由于确定作用机制对于将这些结果转化为临床环境至关重要，因此在这项研究中，我们采用了一种无偏见的蛋白质组学方法。非依赖性数据获取质谱蛋白质组学允许鉴定 190 种蛋白质，其丰度被 TAT-Cx43 改变。我们的结果与 Src 抑制作为 TAT-Cx43 的作用机制一致，并揭示了抗肿瘤效应物，如 p120 连环蛋白。几种蛋白质丰度的变化表明，TAT-Cx43 还可能影响大脑微环境。重要的是，TAT-Cx43 降低其丰度的蛋白质与 GBM 患者在临床数据集中的生存改善相关，而 TAT-Cx43 增加其丰度的蛋白质与生存时间缩短无关，这支持了其在临床试验中的应用。
