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

Research output: Contribution to journalArticle

4 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

Fingerprint

Geranyltranstransferase
Glioblastoma
Alendronate
zoledronic acid
Maintenance
Biosynthesis
Stem cells
Cholesterol
RNA
RNA Sequence Analysis
Messenger RNA
Terpenes
Enzymes
Microarrays
Pharmaceutical Preparations
Small Interfering RNA
Tumors
Genes
Drug Delivery Systems
Embryonic Stem Cells

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Kim, H. Y., Kim, D. K., Bae, S. H., Gwak, H. R., Jeon, J. H., Kim, J. K., ... 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
Kim, Hee Yeon ; Kim, Dong Keon ; Bae, Seung Hyun ; Gwak, Hye Ran ; Jeon, Ji Hoon ; Kim, Jong Kwang ; Lee, Byung Il ; You, Hye Jin ; Shin, Dong Hoon ; Kim, Young Ho ; Kim, Soo Youl ; Han, Sung Sik ; Shim, Jin Kyoung ; Lee, Ji Hyun ; Kang, Seok Gu ; Jang, Hyonchol. / Farnesyl diphosphate synthase is important for the maintenance of glioblastoma stemness. In: Experimental and Molecular Medicine. 2018 ; Vol. 50, No. 10.
@article{3a0146932aa74a3db0711f189bbb594f,
title = "Farnesyl diphosphate synthase is important for the maintenance of glioblastoma stemness",
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.",
author = "Kim, {Hee Yeon} and Kim, {Dong Keon} and Bae, {Seung Hyun} and Gwak, {Hye Ran} and Jeon, {Ji Hoon} and Kim, {Jong Kwang} and Lee, {Byung Il} and You, {Hye Jin} and Shin, {Dong Hoon} and Kim, {Young Ho} and Kim, {Soo Youl} and Han, {Sung Sik} and Shim, {Jin Kyoung} and Lee, {Ji Hyun} and Kang, {Seok Gu} and Hyonchol Jang",
year = "2018",
month = "10",
day = "1",
doi = "10.1038/s12276-018-0166-2",
language = "English",
volume = "50",
journal = "Experimental and Molecular Medicine",
issn = "1226-3613",
publisher = "Korean Society of Med. Biochemistry and Mol. Biology",
number = "10",

}

Kim, HY, Kim, DK, Bae, SH, Gwak, HR, Jeon, JH, Kim, JK, Lee, BI, You, HJ, Shin, DH, Kim, YH, Kim, SY, Han, SS, Shim, JK, Lee, JH, Kang, SG & Jang, H 2018, 'Farnesyl diphosphate synthase is important for the maintenance of glioblastoma stemness', Experimental and Molecular Medicine, vol. 50, no. 10, 137. https://doi.org/10.1038/s12276-018-0166-2

Farnesyl diphosphate synthase is important for the maintenance of glioblastoma stemness. / Kim, Hee Yeon; Kim, Dong Keon; Bae, Seung Hyun; Gwak, Hye Ran; Jeon, Ji Hoon; Kim, Jong Kwang; Lee, Byung Il; You, Hye Jin; Shin, Dong Hoon; Kim, Young Ho; Kim, Soo Youl; Han, Sung Sik; Shim, Jin Kyoung; Lee, Ji Hyun; Kang, Seok Gu; Jang, Hyonchol.

In: Experimental and Molecular Medicine, Vol. 50, No. 10, 137, 01.10.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Farnesyl diphosphate synthase is important for the maintenance of glioblastoma stemness

AU - Kim, Hee Yeon

AU - Kim, Dong Keon

AU - Bae, Seung Hyun

AU - Gwak, Hye Ran

AU - Jeon, Ji Hoon

AU - Kim, Jong Kwang

AU - Lee, Byung Il

AU - You, Hye Jin

AU - Shin, Dong Hoon

AU - Kim, Young Ho

AU - Kim, Soo Youl

AU - Han, Sung Sik

AU - Shim, Jin Kyoung

AU - Lee, Ji Hyun

AU - Kang, Seok Gu

AU - Jang, Hyonchol

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85055072100&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85055072100&partnerID=8YFLogxK

U2 - 10.1038/s12276-018-0166-2

DO - 10.1038/s12276-018-0166-2

M3 - Article

C2 - 30333528

AN - SCOPUS:85055072100

VL - 50

JO - Experimental and Molecular Medicine

JF - Experimental and Molecular Medicine

SN - 1226-3613

IS - 10

M1 - 137

ER -