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

Munki Choo1, Van-Hieu Mai1, Han Sun Kim1, Dong-Hwa Kim1, Ja-Lok Ku2, Sang Kook Lee1, Chul‐Kee Park3, Yong Jin An1, Sunghyouk Park1
1 Natural Product Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Korea
2 Korean Cell Line Bank, Laboratory of Cell Biology, Cancer Research Institute, College of Medicine, Seoul National University, Seoul 03080, Korea
3 Department of Neurosurgery, College of Medicine, Seoul National University, Seoul 03080, Korea
Correspondence to: Yong Jin An:, Sunghyouk Park:,
DOI: 10.1038/s41401-022-00984-6
Received: 14 April 2022
Accepted: 12 August 2022
Advance online: 13 September 2022


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.
Keywords: glioblastoma; temozolomide resistance; cell shape; lipid metabolism; SREBP; fatostatin

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