Glycolysis inhibitors as a potential therapeutic option to treat aggressive neuroblastoma expressing GLUT1.
OBJECTIVE
Increased glycolysis is among the biochemical characteristics of cancerous tissue. The glucose transporter isoform 1 (GLUT1) gene encodes a key factor for glucose transport into cancerous tissue. However, the expression and functional significance of GLUT1 in neuroblastoma have not been fully characterized. Therefore, we investigated the association of GLUT1 expression with clinical outcomes in patients with neuroblastoma using immunohistochemical staining for GLUT1 in neuroblastoma tissues. We also assessed the efficacy of glycolysis inhibition as an anticancer treatment in neuroblastoma cell lines with altered expression of GLUT1.


METHODS
We obtained total RNA from cancerous tissue by microdissection in 47 patients with neuroblastoma. GLUT1 expression levels were evaluated by quantitative real-time polymerase chain reaction. We analyzed the association of GLUT1 expression levels with clinical outcomes. We also examined changes in GLUT1 expression and proliferative responses in vitro using 4 neuroblastoma cell lines treated with a glycolysis inhibitor, 3-Bromopyruvate acid.


RESULTS
Elevated GLUT1 expression was associated with poor prognosis. Moreover, elevated GLUT1 expression independently predicted overall survival. Immunohistochemical analysis showed that GLUT1 expression tended to be localized to the centers of neuroblastoma cell nests. Our in vitro studies showed that 3-Bromopyruvate acid significantly suppressed the proliferation of neuroblastoma cells with high GLUT1 gene expression compared with those with low expression.


CONCLUSIONS
Glycolysis inhibitors are a potential therapeutic option for treating aggressive tumors expressing GLUT1.
Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan. cohey@clin.medic.mie-u.ac.jp
Kohei
K
Matsushita
Keiichi
K
Uchida
Susumu
S
Saigusa
Shozo
S
Ide
Kiyoshi
K
Hashimoto
Yuki
Y
Koike
Kohei
K
Otake
Mikihiro
M
Inoue
Koji
K
Tanaka
Masato
M
Kusunoki
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D002648:Child; D002675:Child, Preschool; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D051272:Glucose Transporter Type 1 / Q000378:metabolism*; D006801:Humans; D007223:Infant; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000601:surgery; D011773:Pyruvates / Q000627:therapeutic use*; D060888:Real-Time Polymerase Chain Reaction; D016019:Survival Analysis; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D051272:Glucose Transporter Type 1; D019394:Ki-67 Antigen; D011773:Pyruvates; C495677:SLC2A1 protein, human; C017092:bromopyruvate