Glucose-6-phosphatase is a key metabolic regulator of glioblastoma invasion.
Glucose-6-phosphatase is a key metabolic regulator of glioblastoma invasion.
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DOI：
10.1158/1541-7786.mcr-14-0106-t
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发表时间：
2014-11
期刊：
影响因子：
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通讯作者：
Quinones-Hinojosa A
中科院分区：
文献类型：
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作者：
Abbadi S;Rodarte JJ;Abutaleb A;Lavell E;Smith CL;Ruff W;Schiller J;Olivi A;Levchenko A;Guerrero-Cazares H;Quinones-Hinojosa A
胶质母细胞瘤（GBM）仍然是成人中最具侵袭性的原发性脑癌。与其他癌症类似，GBM 细胞经历代谢重编程以促进增殖和存活。糖酵解抑制广泛用于靶向此类重编程。然而，GBM 中糖酵解抑制的稳定性仍不清楚，尤其是在缺氧的肿瘤微环境中。在这项研究中，确定与正常大脑相比，GBM 中葡萄糖-6-磷酸酶-α (G6PC/G6Pase) 的表达升高。人源性脑肿瘤起始细胞 (BTIC) 利用这种酶来抵消 2-脱氧-D-葡萄糖 (2DG) 诱导的糖酵解抑制并维持恶性进展。 G6PC 的下调使大多数细胞无法在糖酵解抑制中存活，并通过激活糖原合酶 (GYS1) 和抑制糖原磷酸化酶 (PYGL) 促进糖原积累。此外，在 G6PC 敲低后存活下来的 BTIC 攻击性较低（迁移、侵袭、增殖减少，星形胶质细胞分化增加）。总的来说，这些发现确立了 G6PC 是一种具有促恶性功能后果的关键酶，这一点此前在 GBM 中尚未报道过，并将其确定为潜在的治疗靶点。
Glioblastoma (GBM) remains the most aggressive primary brain cancer in adults. Similar to other cancers, GBM cells undergo metabolic reprogramming to promote proliferation and survival. Glycolytic inhibition is widely used to target such reprogramming. However, the stability of glycolytic inhibition in GBM remains unclear especially in a hypoxic tumor microenvironment. In this study, it was determined that glucose-6-phosphatase-α (G6PC/G6Pase) expression is elevated in GBM when compared to normal brain. Human-derived brain tumor initiating cells (BTICs) utilize this enzyme to counteract glycolytic inhibition induced by 2-Deoxy-D-glucose (2DG) and sustain malignant progression. Down-regulation of G6PC renders the majority of these cells unable to survive glycolytic inhibition, and promotes glycogen accumulation through the activation of glycogen synthase (GYS1) and inhibition of glycogen phosphorylase (PYGL). Moreover, BTICs that survive G6PC knockdown are less aggressive (reduced migration, invasion, proliferation, and increased astrocytic differentiation). Collectively, these findings establish G6PC as a key enzyme with pro-malignant functional consequences that has not been previously reported in GBM and identify it as a potential therapeutic target.