Involvement of cell shape and lipid metabolism in glioblastoma resistance to temozolomide

被引:0
|
作者
Munki Choo
Van-Hieu Mai
Han Sun Kim
Dong-Hwa Kim
Ja-Lok Ku
Sang Kook Lee
Chul‑Kee Park
Yong Jin An
Sunghyouk Park
机构
[1] Seoul National University,Natural Product Research Institute, College of Pharmacy
[2] Seoul National University,Korean Cell Line Bank, Laboratory of Cell Biology, Cancer Research Institute, College of Medicine
[3] Seoul National University,Department of Neurosurgery, College of Medicine
来源
Acta Pharmacologica Sinica | 2023年 / 44卷
关键词
glioblastoma; temozolomide resistance; cell shape; lipid metabolism; SREBP; fatostatin;
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学科分类号
摘要
Temozolomide (TMZ) has been used as standard-of-care for glioblastoma multiforme (GBM), but the resistance to TMZ develops quickly and frequently. Thus, more studies are needed to elucidate the resistance mechanisms. In the current study, we investigated the relationship among the three important phenotypes, namely TMZ-resistance, cell shape and lipid metabolism, in GBM cells. We first observed the distinct difference in cell shapes between TMZ-sensitive (U87) and resistant (U87R) GBM cells. We then conducted NMR-based lipid metabolomics, which revealed a significant increase in cholesterol and fatty acid synthesis as well as lower lipid unsaturation in U87R cells. Consistent with the lipid changes, U87R cells exhibited significantly lower membrane fluidity. The transcriptomic analysis demonstrated that lipid synthesis pathways through SREBP were upregulated in U87R cells, which was confirmed at the protein level. Fatostatin, an SREBP inhibitor, and other lipid pathway inhibitors (C75, TOFA) exhibited similar or more potent inhibition on U87R cells compared to sensitive U87 cells. The lower lipid unsaturation ratio, membrane fluidity and higher fatostatin sensitivity were all recapitulated in patient-derived TMZ-resistant primary cells. The observed ternary relationship among cell shape, lipid composition, and TMZ-resistance may be applicable to other drug-resistance cases. SREBP and fatostatin are suggested as a promising target-therapeutic agent pair for drug-resistant glioblastoma.
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页码:670 / 679
页数:9
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