Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Neoplasma. 2023 Apr;70(2):260-271. doi: 10.4149/neo_2023_221126N1140.
Metabolic reprogramming is a common feature of glioblastoma (GBM) progression and metastasis. Altered lipid metabolism is one of the most prominent metabolic alterations in cancer. Understanding the links between phospholipid remodeling and GBM tumorigenesis may help develop new anticancer strategies and improve treatments to overcome drug resistance. We used metabolomic and transcriptomic analyses to systematically investigate metabolic and molecular changes in low-grade glioma (LGG) and GBM. We then re-established the reprogrammed metabolic flux and membrane lipid composition in GBM based on metabolomic and transcriptomic analyses. By inhibiting Aurora A kinase via RNA interference (RNAi) and inhibitor treatment, we investigated the effect of Aurora A kinase on phospholipid reprogramming LPCAT1 enzyme expression and GBM cell proliferation in vitro and in vivo. We found that GBM displayed aberrant glycerophospholipid and glycerolipid metabolism compared with LGG. Metabolic profiling indicated that fatty acid synthesis and uptake for phospholipid synthesis were significantly increased in GBM compared to LGG. The unsaturated phosphatidylcholine (PC) and phosphatidylethanolamine (PE) levels were significantly decreased in GBM compared to LGG. The expression level of LPCAT1, which is required for the synthesis of saturated PC and PE, was upregulated in GBM, and the expression of LPCAT4, which is required for the synthesis of unsaturated PC and PE, was downregulated in GBM. Notably, the inhibition of Aurora A kinase by shRNA knockdown and treatment with Aurora A kinase inhibitors such as Alisertib, AMG900, or AT9283 upregulated LPCAT1 mRNA and protein expression in vitro. In vivo, the inhibition of Aurora A kinase with Alisertib increased LPCAT1 protein expression. Phospholipid remodeling and a reduction in unsaturated membrane lipid components were found in GBM. Aurora A kinase inhibition increased LPCAT1 expression and suppressed GBM cell proliferation. The combination of Aurora kinase inhibition with LPCAT1 inhibition may exert promising synergistic effects on GBM.
代谢重编程是胶质母细胞瘤（GBM）进展和转移的共同特征。脂质代谢的改变是癌症中最显著的代谢改变之一。了解磷脂重塑与 GBM 肿瘤发生之间的联系，可能有助于开发新的抗癌策略，并改善治疗方法以克服耐药性。我们使用代谢组学和转录组学分析系统地研究了低级别胶质瘤（LGG）和 GBM 中的代谢和分子变化。然后，我们根据代谢组学和转录组学分析，在 GBM 中重新建立了重编程的代谢通量和膜脂质组成。通过 RNA 干扰（RNAi）和抑制剂处理抑制 Aurora A 激酶，我们研究了 Aurora A 激酶对磷脂重编程 LPCAT1 酶表达和 GBM 细胞在体外和体内增殖的影响。我们发现，与 LGG 相比，GBM 显示出异常的甘油磷脂和甘油酯代谢。代谢谱分析表明，与 LGG 相比，GBM 中用于磷脂合成的脂肪酸合成和摄取显著增加。与 LGG 相比，GBM 中的不饱和磷脂酰胆碱（PC）和磷脂酰乙醇胺（PE）水平显著降低。LPCAT1 的表达水平上调，该酶是合成饱和 PC 和 PE 所必需的，而 LPCAT4 的表达水平下调，该酶是合成不饱和 PC 和 PE 所必需的。值得注意的是，通过 shRNA 敲低抑制 Aurora A 激酶和用 Aurora A 激酶抑制剂（如 Alisertib、AMG900 或 AT9283）处理均可在体外上调 LPCAT1 mRNA 和蛋白表达。在体内，用 Alisertib 抑制 Aurora A 激酶可增加 LPCAT1 蛋白表达。在 GBM 中发现了磷脂重塑和不饱和膜脂质成分减少。Aurora A 激酶抑制增加了 LPCAT1 表达并抑制了 GBM 细胞增殖。Aurora 激酶抑制与 LPCAT1 抑制的联合应用可能对 GBM 产生有前景的协同作用。
