Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut 1107 2020, Lebanon.
Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409, USA.
Int J Mol Sci. 2023 Sep 14;24(18):14069. doi: 10.3390/ijms241814069.
Glioblastoma Multiforme (GBM) is the most aggressive form of malignant brain tumor. The median survival rate does not exceed two years, indicating an imminent need to develop novel therapies. The atypical adamantyl retinoid ST1926 induces apoptosis and growth inhibition in different cancer types. We have shown that ST1926 is an inhibitor of the catalytic subunit of DNA polymerase alpha (POLA1), which is involved in initiating DNA synthesis in eukaryotic cells. POLA1 levels are elevated in GBM versus normal brain tissues. Therefore, we studied the antitumor effects of ST1926 in several human GBM cell lines. We further explored the global protein expression profiles in GBM cell lines using liquid chromatography coupled with tandem mass spectrometry to identify new targets of ST1926. Low sub-micromolar concentrations of ST1926 potently decreased cell viability, induced cell damage and apoptosis, and reduced POLA1 protein levels in GBM cells. The proteomics profiles revealed 197 proteins significantly differentially altered upon ST1926 treatment of GBM cells involved in various cellular processes. We explored the differential gene and protein expression of significantly altered proteins in GBM compared to normal brain tissues.
多形性胶质母细胞瘤（GBM）是最具侵袭性的恶性脑肿瘤。中位生存时间不超过两年，表明迫切需要开发新的治疗方法。非典型金刚烷类视黄醇 ST1926 可诱导不同癌症类型的细胞凋亡和生长抑制。我们已经表明，ST1926 是 DNA 聚合酶 α（POLA1）催化亚基的抑制剂，该酶参与真核细胞中 DNA 合成的起始。GBM 与正常脑组织相比，POLA1 水平升高。因此，我们研究了 ST1926 在几种人 GBM 细胞系中的抗肿瘤作用。我们进一步使用液相色谱-串联质谱联用技术研究了 GBM 细胞系中的全局蛋白质表达谱，以鉴定 ST1926 的新靶标。低亚微摩尔浓度的 ST1926 可强烈降低 GBM 细胞的活力，诱导细胞损伤和凋亡，并降低 POLA1 蛋白水平。蛋白质组学图谱显示，GBM 细胞中经 ST1926 处理后有 197 种蛋白质显著改变，涉及各种细胞过程。我们探讨了与正常脑组织相比，GBM 中差异表达基因和蛋白质的差异。
