通过增强脂肪酸氧化中线粒体活性，重新编程花生四烯酸代谢可使胶质母细胞瘤对替莫唑胺产生耐药性。
Reprogramming of arachidonate metabolism confers temozolomide resistance to glioblastoma through enhancing mitochondrial activity in fatty acid oxidation.
机构信息
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei, Taiwan, 110.
Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan.
出版信息
J Biomed Sci. 2022 Mar 25;29(1):21. doi: 10.1186/s12929-022-00804-3.
BACKGROUND
Sp1 is involved in the recurrence of glioblastoma (GBM) due to the acquirement of resistance to temozolomide (TMZ). Particularly, the role of Sp1 in metabolic reprogramming for drug resistance remains unknown.
METHODS
RNA-Seq and mass spectrometry were used to analyze gene expression and metabolites amounts in paired GBM specimens (primary vs. recurrent) and in paired GBM cells (sensitive vs. resistant). ω-3/6 fatty acid and arachidonic acid (AA) metabolism in GBM patients were analyzed by targeted metabolome. Mitochondrial functions were determined by Seahorse XF Mito Stress Test, RNA-Seq, metabolome and substrate utilization for producing ATP. Therapeutic options targeting prostaglandin (PG) E2 in TMZ-resistant GBM were validated in vitro and in vivo.
RESULTS
Among the metabolic pathways, Sp1 increased the prostaglandin-endoperoxide synthase 2 expression and PGE2 production in TMZ-resistant GBM. Mitochondrial genes and metabolites were obviously increased by PGE2, and these characteristics were required for developing resistance in GBM cells. For inducing TMZ resistance, PGE2 activated mitochondrial functions, including fatty acid β-oxidation (FAO) and tricarboxylic acid (TCA) cycle progression, through PGE2 receptors, E-type prostanoid (EP)1 and EP3. Additionally, EP1 antagonist ONO-8713 inhibited the survival of TMZ-resistant GBM synergistically with TMZ.
CONCLUSION
Sp1-regulated PGE2 production activates FAO and TCA cycle in mitochondria, through EP1 and EP3 receptors, resulting in TMZ resistance in GBM. These results will provide us a new strategy to attenuate drug resistance or to re-sensitize recurred GBM.
背景
Sp1 参与了胶质母细胞瘤（GBM）的复发，因为其对替莫唑胺（TMZ）的耐药性的获得。特别是，Sp1 在代谢重编程中对耐药性的作用仍然未知。
方法
使用 RNA-Seq 和质谱分析了配对的 GBM 标本（原发性与复发性）和配对的 GBM 细胞（敏感与耐药）中的基因表达和代谢物含量。通过靶向代谢组学分析 GBM 患者的 ω-3/6 脂肪酸和花生四烯酸（AA）代谢。通过 Seahorse XF Mito Stress Test、RNA-Seq、代谢组学和用于产生 ATP 的底物利用来确定线粒体功能。在体外和体内验证了针对 TMZ 耐药性 GBM 中前列腺素（PG）E2 的治疗选择。
结果
在代谢途径中，Sp1 增加了 TMZ 耐药性 GBM 中的前列腺素内过氧化物合酶 2 的表达和 PGE2 的产生。PGE2 明显增加了线粒体基因和代谢物，这些特征是 GBM 细胞产生耐药性所必需的。为了诱导 TMZ 耐药性，PGE2 通过 PGE2 受体 EP1 和 EP3 激活了线粒体功能，包括脂肪酸 β-氧化（FAO）和三羧酸（TCA）循环进展。此外，EP1 拮抗剂 ONO-8713 与 TMZ 协同抑制 TMZ 耐药性 GBM 的存活。
结论
Sp1 调节的 PGE2 产生通过 EP1 和 EP3 受体激活线粒体中的 FAO 和 TCA 循环，导致 GBM 中的 TMZ 耐药性。这些结果将为我们提供一种新的策略来减弱耐药性或重新敏感复发的 GBM。
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