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Exp Mol Med. 2018 Oct 17;50(10):137. doi: 10.1038/s12276-018-0166-2.

Farnesyl diphosphate synthase is important for the maintenance of glioblastoma stemness.

Author information

1
Research Institute, National Cancer Center, Goyang, 10408, Republic of Korea.
2
Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, Goyang, 10408, Republic of Korea.
3
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea.
4
Center for Liver Cancer, National Cancer Center, Goyang, 10408, Republic of Korea.
5
Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Korea.
6
Research Institute, National Cancer Center, Goyang, 10408, Republic of Korea. hjang@ncc.re.kr.
7
Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, Goyang, 10408, Republic of Korea. hjang@ncc.re.kr.

Abstract

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.

PMID:
30333528
PMCID:
PMC6193020
DOI:
10.1038/s12276-018-0166-2
[Indexed for MEDLINE]
Free PMC Article

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