Farnesyl diphosphate synthase is important for the maintenance of glioblastoma stemness

Hee Yeon Kim, Dong Keon Kim, Seung Hyun Bae, Hye Ran Gwak, Ji Hoon Jeon, Jong Kwang Kim, Byung Il Lee, Hye Jin You, Dong Hoon Shin, Young Ho Kim, Soo Youl Kim, Sung Sik Han, Jin Kyoung Shim, Ji Hyun Lee, Seok Gu Kang, Hyonchol Jang

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12 Citations (Scopus)

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.

Original languageEnglish
Article number137
JournalExperimental and Molecular Medicine
Volume50
Issue number10
DOIs
Publication statusPublished - 2018 Oct 1

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

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    Kim, H. Y., Kim, D. K., Bae, S. H., Gwak, H. R., Jeon, J. H., Kim, J. K., Lee, B. I., You, H. J., Shin, D. H., Kim, Y. H., Kim, S. Y., Han, S. S., Shim, J. K., Lee, J. H., Kang, S. G., & Jang, H. (2018). Farnesyl diphosphate synthase is important for the maintenance of glioblastoma stemness. Experimental and Molecular Medicine, 50(10), [137]. https://doi.org/10.1038/s12276-018-0166-2