Department of Radiology and Biomedical Imaging, University of California San Francisco, 1700 4th Street, San Francisco, CA, 94158, USA.
Department of Neurological Surgery, University of California, San Francisco, USA.
Sci Rep. 2023 Mar 30;13(1):5190. doi: 10.1038/s41598-023-32463-1.
TERT promoter mutations are a hallmark of glioblastoma (GBM). Accordingly, TERT and GABPB1, a subunit of the upstream mutant TERT promoter transcription factor GABP, are being considered as promising therapeutic targets in GBM. We recently reported that the expression of TERT or GABP1 modulates flux via the pentose phosphate pathway (PPP). Here, we investigated whether C magnetic resonance spectroscopy (MRS) of hyperpolarized (HP) δ- [1-C]gluconolactone can serve to image the reduction in PPP flux following TERT or GABPB1 silencing. We investigated two different human GBM cell lines stably expressing shRNAs targeting TERT or GABPB1, as well as doxycycline-inducible shTERT or shGABPB1cells. MRS studies were performed on live cells and in vivo tumors, and dynamic sets of C MR spectra were acquired following injection of HP δ-[1-C]gluconolactone. HP 6-phosphogluconolactone (6PG), the product of δ-[1-C]gluconolactone via the PPP, was significantly reduced in TERT or GABPB1-silenced cells or tumors compared to controls in all our models. Furthermore, a positive correlation between TERT expression and 6PG levels was observed. Our data indicate that HP δ-[1-C]gluconolactone, an imaging tool with translational potential, could serve to monitor TERT expression and its silencing with therapies that target either TERT or GABPB1 in mutant TERT promoter GBM patients.
TERT 启动子突变是胶质母细胞瘤（GBM）的一个标志。因此，TERT 和 GABPB1（上游突变 TERT 启动子转录因子 GABP 的一个亚基）被认为是 GBM 中有前途的治疗靶点。我们最近报道，TERT 或 GABP1 的表达调节戊糖磷酸途径（PPP）的通量。在这里，我们研究了极化（HP）δ-[1-C]葡萄糖酸内酯的 C 磁共振波谱（MRS）是否可以用于成像 TERT 或 GABPB1 沉默后 PPP 通量的降低。我们研究了两种不同的稳定表达靶向 TERT 或 GABPB1 的短发夹 RNA（shRNA）的人 GBM 细胞系，以及诱导型 shTERT 或 shGABPB1 细胞。在活细胞和体内肿瘤上进行了 MRS 研究，并在注射 HP δ-[1-C]葡萄糖酸内酯后获得了动态的 C MR 谱集。与对照相比，在所有模型中，在 TERT 或 GABPB1 沉默的细胞或肿瘤中，HP 6-磷酸葡萄糖酸内酯（6PG），即 PPP 中 δ-[1-C]葡萄糖酸内酯的产物，明显减少。此外，还观察到 TERT 表达与 6PG 水平之间存在正相关。我们的数据表明，HP δ-[1-C]葡萄糖酸内酯是一种具有转化潜力的成像工具，可用于监测 TERT 表达及其在突变 TERT 启动子 GBM 患者中靶向 TERT 或 GABPB1 的治疗中的沉默。
