Glutaminase 2 expression is associated with regional heterogeneity of 5-aminolevulinic acid fluorescence in glioblastoma

Sojin Kim; Ja Eun Kim; Yong Hwy Kim; Taeyoung Hwang; Sung Kwon Kim; Wen Jun Xu; Jong Yeon Shin; Jong Il Kim; Hyoungseon Choi; Hee Chan Kim; Hye Rim Cho; Anna Choi; Tamrin Chowdhury; Youngbeom Seo; Yun Sik Dho; Jin Wook Kim; Dong Gyu Kim; Sung Hye Park; Hyeonjin Kim; Seung Hong Choi; Sunghyouk Park; Se Hoon Lee; Chul Kee Park

doi:10.1038/s41598-017-12557-3

Glutaminase 2 expression is associated with regional heterogeneity of 5-aminolevulinic acid fluorescence in glioblastoma

Sojin Kim, Ja Eun Kim, Yong Hwy Kim, Taeyoung Hwang, Sung Kwon Kim, Wen Jun Xu, Jong Yeon Shin, Jong Il Kim, Hyoungseon Choi, Hee Chan Kim, Hye Rim Cho, Anna Choi, Tamrin Chowdhury, Youngbeom Seo, Yun Sik Dho, Jin Wook Kim, Dong Gyu Kim, Sung Hye Park, Hyeonjin Kim, Seung Hong ChoiSunghyouk Park, Se Hoon Lee, Chul Kee Park

Research output: Contribution to journal › Article › peer-review

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Abstract

Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) is now a widely-used modality for glioblastoma (GBM) treatment. However, intratumoral heterogeneity of fluorescence intensity may reflect different onco-metabolic programs. Here, we investigated the metabolic mechanism underlying the heterogeneity of 5-ALA fluorescence in GBM. Using an in-house developed fluorescence quantification system for tumor tissues, we collected 3 types of GBM tissues on the basis of their fluorescence intensity, which was characterized as strong, weak, and none. Expression profiling by RNA-sequencing revealed 77 genes with a proportional relationship and 509 genes with an inverse relationship between gene expression and fluorescence intensity. Functional analysis and in vitro experiments confirmed glutaminase 2 (GLS2) as a key gene associated with the fluorescence heterogeneity. Subsequent metabolite profiling discovered that insufficient NADPH due to GLS2 underexpression was responsible for the delayed metabolism of 5-ALA and accumulation of protoporphyrin IX (PpIX) in the high fluorescence area. The expression level of GLS2 and related NADPH production capacity is associated with the regional heterogeneity of 5-ALA fluorescence in GBM.

Original language	English
Article number	12221
Journal	Scientific Reports
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/s41598-017-12557-3
State	Published - 1 Dec 2017
Externally published	Yes

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Kim, S., Kim, J. E., Kim, Y. H., Hwang, T., Kim, S. K., Xu, W. J., Shin, J. Y., Kim, J. I., Choi, H., Kim, H. C., Cho, H. R., Choi, A., Chowdhury, T., Seo, Y., Dho, Y. S., Kim, J. W., Kim, D. G., Park, S. H., Kim, H., ... Park, C. K. (2017). Glutaminase 2 expression is associated with regional heterogeneity of 5-aminolevulinic acid fluorescence in glioblastoma. Scientific Reports, 7(1), Article 12221. https://doi.org/10.1038/s41598-017-12557-3

@article{621b4b0d27634139b15d0b1874b1762d,

title = "Glutaminase 2 expression is associated with regional heterogeneity of 5-aminolevulinic acid fluorescence in glioblastoma",

abstract = "Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) is now a widely-used modality for glioblastoma (GBM) treatment. However, intratumoral heterogeneity of fluorescence intensity may reflect different onco-metabolic programs. Here, we investigated the metabolic mechanism underlying the heterogeneity of 5-ALA fluorescence in GBM. Using an in-house developed fluorescence quantification system for tumor tissues, we collected 3 types of GBM tissues on the basis of their fluorescence intensity, which was characterized as strong, weak, and none. Expression profiling by RNA-sequencing revealed 77 genes with a proportional relationship and 509 genes with an inverse relationship between gene expression and fluorescence intensity. Functional analysis and in vitro experiments confirmed glutaminase 2 (GLS2) as a key gene associated with the fluorescence heterogeneity. Subsequent metabolite profiling discovered that insufficient NADPH due to GLS2 underexpression was responsible for the delayed metabolism of 5-ALA and accumulation of protoporphyrin IX (PpIX) in the high fluorescence area. The expression level of GLS2 and related NADPH production capacity is associated with the regional heterogeneity of 5-ALA fluorescence in GBM.",

author = "Sojin Kim and Kim, \{Ja Eun\} and Kim, \{Yong Hwy\} and Taeyoung Hwang and Kim, \{Sung Kwon\} and Xu, \{Wen Jun\} and Shin, \{Jong Yeon\} and Kim, \{Jong Il\} and Hyoungseon Choi and Kim, \{Hee Chan\} and Cho, \{Hye Rim\} and Anna Choi and Tamrin Chowdhury and Youngbeom Seo and Dho, \{Yun Sik\} and Kim, \{Jin Wook\} and Kim, \{Dong Gyu\} and Park, \{Sung Hye\} and Hyeonjin Kim and Choi, \{Seung Hong\} and Sunghyouk Park and Lee, \{Se Hoon\} and Park, \{Chul Kee\}",

note = "Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

month = dec,

day = "1",

doi = "10.1038/s41598-017-12557-3",

language = "English",

volume = "7",

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Kim, S, Kim, JE, Kim, YH, Hwang, T, Kim, SK, Xu, WJ, Shin, JY, Kim, JI, Choi, H, Kim, HC, Cho, HR, Choi, A, Chowdhury, T, Seo, Y, Dho, YS, Kim, JW, Kim, DG, Park, SH, Kim, H, Choi, SH, Park, S, Lee, SH & Park, CK 2017, 'Glutaminase 2 expression is associated with regional heterogeneity of 5-aminolevulinic acid fluorescence in glioblastoma', Scientific Reports, vol. 7, no. 1, 12221. https://doi.org/10.1038/s41598-017-12557-3

TY - JOUR

T1 - Glutaminase 2 expression is associated with regional heterogeneity of 5-aminolevulinic acid fluorescence in glioblastoma

AU - Kim, Sojin

AU - Kim, Ja Eun

AU - Kim, Yong Hwy

AU - Hwang, Taeyoung

AU - Kim, Sung Kwon

AU - Xu, Wen Jun

AU - Shin, Jong Yeon

AU - Kim, Jong Il

AU - Choi, Hyoungseon

AU - Kim, Hee Chan

AU - Cho, Hye Rim

AU - Choi, Anna

AU - Chowdhury, Tamrin

AU - Seo, Youngbeom

AU - Dho, Yun Sik

AU - Kim, Jin Wook

AU - Kim, Dong Gyu

AU - Park, Sung Hye

AU - Kim, Hyeonjin

AU - Choi, Seung Hong

AU - Park, Sunghyouk

AU - Lee, Se Hoon

AU - Park, Chul Kee

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) is now a widely-used modality for glioblastoma (GBM) treatment. However, intratumoral heterogeneity of fluorescence intensity may reflect different onco-metabolic programs. Here, we investigated the metabolic mechanism underlying the heterogeneity of 5-ALA fluorescence in GBM. Using an in-house developed fluorescence quantification system for tumor tissues, we collected 3 types of GBM tissues on the basis of their fluorescence intensity, which was characterized as strong, weak, and none. Expression profiling by RNA-sequencing revealed 77 genes with a proportional relationship and 509 genes with an inverse relationship between gene expression and fluorescence intensity. Functional analysis and in vitro experiments confirmed glutaminase 2 (GLS2) as a key gene associated with the fluorescence heterogeneity. Subsequent metabolite profiling discovered that insufficient NADPH due to GLS2 underexpression was responsible for the delayed metabolism of 5-ALA and accumulation of protoporphyrin IX (PpIX) in the high fluorescence area. The expression level of GLS2 and related NADPH production capacity is associated with the regional heterogeneity of 5-ALA fluorescence in GBM.

AB - Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) is now a widely-used modality for glioblastoma (GBM) treatment. However, intratumoral heterogeneity of fluorescence intensity may reflect different onco-metabolic programs. Here, we investigated the metabolic mechanism underlying the heterogeneity of 5-ALA fluorescence in GBM. Using an in-house developed fluorescence quantification system for tumor tissues, we collected 3 types of GBM tissues on the basis of their fluorescence intensity, which was characterized as strong, weak, and none. Expression profiling by RNA-sequencing revealed 77 genes with a proportional relationship and 509 genes with an inverse relationship between gene expression and fluorescence intensity. Functional analysis and in vitro experiments confirmed glutaminase 2 (GLS2) as a key gene associated with the fluorescence heterogeneity. Subsequent metabolite profiling discovered that insufficient NADPH due to GLS2 underexpression was responsible for the delayed metabolism of 5-ALA and accumulation of protoporphyrin IX (PpIX) in the high fluorescence area. The expression level of GLS2 and related NADPH production capacity is associated with the regional heterogeneity of 5-ALA fluorescence in GBM.

UR - https://www.scopus.com/pages/publications/85029765058

U2 - 10.1038/s41598-017-12557-3

DO - 10.1038/s41598-017-12557-3

M3 - Article

C2 - 28939850

AN - SCOPUS:85029765058

SN - 2045-2322

VL - 7

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 12221

ER -

Glutaminase 2 expression is associated with regional heterogeneity of 5-aminolevulinic acid fluorescence in glioblastoma

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