Glioblastoma is a highly malignant tumor that easily acquires resistance to treatment. The stem-cell-like character (stemness) has been thought to be closely associated with the treatment resistance of glioblastoma cells. In this study, we determined that farnesyl diphosphate synthase (FDPS), a key enzyme in isoprenoid biosynthesis, plays an important role in maintaining glioblastoma stemness. A comparison of the mRNA expression in patient-derived glioblastoma sphere cells, which maintain stemness, and their differentiated counterparts, which lose stemness, via RNA sequencing showed that most of the altered genes were networked in the cholesterol biosynthesis pathway. We screened Federal Drug Administration (FDA)-approved drugs targeting specific enzymes in the cholesterol biosynthesis pathway for their ability to inhibit glioblastoma sphere formation. Inhibitors of FDPS, such as alendronate and zoledronate, significantly reduced the formation of glioblastoma spheres, and alendronate was effective at a lower molar concentration than zoledronate. Knockdown of FDPS using short hairpin RNA also completely inhibited the formation of secondary spheres. FDPS mRNA in patients with glioblastoma was associated with malignancy in three independent microarray data sets. RNA sequencing showed that alendronate treatment reduced the embryonic stem cell signature and activated development- and necrosis-related pathways in glioblastoma spheres. These results suggest that FDPS is important for the maintenance of glioblastoma stemness and that alendronate, a drug widely used to treat osteoporosis, can be repositioned to treat glioblastoma.
Bibliographical noteFunding Information:
We thank Mi Ae Kim of the Imaging Core (National Cancer Center) for her expert assistance with confocal imaging and the Bioinformatics Core (National Cancer Center) for supportive analysis of RNA sequencing data. This study was funded by grants from the National Cancer Center, Korea (NCC-1610190, NCC-1810990, and NCC-1810292 to H.J. and NCC-1710190 to SSH) and by a grant from National Research Foundation of Korea (NRF-2017R1A2B4009200 to H.J.). H.Y.K. was supported by the International Cooperation & Education Program (#NCCRI-NCCI 52210-52211, 2017) of National Cancer Center, Korea.
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Molecular Biology
- Clinical Biochemistry