Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030, USA.
Department of Translational Medical Sciences, College of Medicine, Texas A&M University Health Science Center, Houston, TX 77030, USA.
Int J Mol Sci. 2024 May 30;25(11):5992. doi: 10.3390/ijms25115992.
IMP dehydrogenase (IMPDH) inhibition has emerged as a new target therapy for glioblastoma multiforme (GBM), which remains one of the most refractory tumors to date. TCGA analyses revealed distinct expression profiles of IMPDH isoenzymes in various subtypes of GBM and low-grade glioma (LGG). To dissect the mechanism(s) underlying the anti-tumor effect of IMPDH inhibition in adult GBM, we investigated how mycophenolic acid (MPA, an IMPDH inhibitor) treatment affected key oncogenic drivers in glioblastoma cells. Our results showed that MPA decreased the expression of telomerase reverse transcriptase (TERT) in both U87 and U251 cells, and the expression of O-methylguanine-DNA methyltransferase (MGMT) in U251 cells. In support, MPA treatment reduced the amount of telomere repeats in U87 and U251 cells. TERT downregulation by MPA was associated with a significant decrease in c-Myc (a TERT transcription activator) in U87 but not U251 cells, and a dose-dependent increase in p53 and CCCTC-binding factor (CTCF) (TERT repressors) in both U87 and U251 cells. In U251 cells, MPA displayed strong cytotoxic synergy with BCNU and moderate synergy with irinotecan, oxaliplatin, paclitaxel, or temozolomide (TMZ). In U87 cells, MPA displayed strong cytotoxic synergy with all except TMZ, acting primarily through the apoptotic pathway. Our work expands the mechanistic potential of IMPDH inhibition to TERT/telomere regulation and reveals a synthetic lethality between MPA and anti-GBM drugs.
肌苷单磷酸脱氢酶（IMPDH）抑制已成为多形性胶质母细胞瘤（GBM）的一种新的靶向治疗方法，GBM 仍然是迄今为止最难治疗的肿瘤之一。TCGA 分析显示，IMP 同工酶在不同亚型的 GBM 和低级别胶质瘤（LGG）中有不同的表达谱。为了剖析 IMPDH 抑制在成人 GBM 中的抗肿瘤作用机制，我们研究了吗替麦考酚酸（MPA，一种 IMPDH 抑制剂）处理如何影响胶质母细胞瘤细胞中的关键致癌驱动因子。我们的结果表明，MPA 降低了 U87 和 U251 细胞中端粒酶逆转录酶（TERT）的表达，以及 U251 细胞中的 O-甲基鸟嘌呤-DNA 甲基转移酶（MGMT）的表达。支持这一结果的是，MPA 处理降低了 U87 和 U251 细胞中端粒重复的数量。MPA 下调 TERT 与 U87 细胞中 c-Myc（TERT 转录激活剂）的显著减少有关，但与 U251 细胞无关，并且与 U87 和 U251 细胞中 p53 和 CCCTC 结合因子（CTCF）（TERT 抑制剂）的剂量依赖性增加有关。在 U251 细胞中，MPA 与 BCNU 显示出强烈的细胞毒性协同作用，与伊立替康、奥沙利铂、紫杉醇或替莫唑胺（TMZ）显示出中度协同作用。在 U87 细胞中，MPA 与除 TMZ 之外的所有药物均显示出强烈的细胞毒性协同作用，主要通过凋亡途径起作用。我们的工作扩展了 IMPDH 抑制的机制潜力，以实现 TERT/端粒调节，并揭示了 MPA 和抗 GBM 药物之间的合成致死性。
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