Cargando…
VDAC2 interacts with PFKP to regulate glucose metabolism and phenotypic reprogramming of glioma stem cells
Plastic phenotype convention between glioma stem cells (GSCs) and non-stem tumor cells (NSTCs) significantly fuels glioblastoma heterogeneity that causes therapeutic failure. Recent progressions indicate that glucose metabolic reprogramming could drive cell fates. However, the metabolic pattern of G...
Autores principales: | , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155247/ https://www.ncbi.nlm.nih.gov/pubmed/30250190 http://dx.doi.org/10.1038/s41419-018-1015-x |
_version_ | 1783357858879897600 |
---|---|
author | Zhou, Kai Yao, Yue-Liang He, Zhi-Cheng Chen, Cong Zhang, Xiao-Ning Yang, Kai-Di Liu, Yu-Qi Liu, Qing Fu, Wen-Juan Chen, Ya-Ping Niu, Qin Ma, Qing-Hua Zhou, Rong Yao, Xiao-Hong Zhang, Xia Cui, You-Hong Bian, Xiu-Wu Shi, Yu Ping, Yi-Fang |
author_facet | Zhou, Kai Yao, Yue-Liang He, Zhi-Cheng Chen, Cong Zhang, Xiao-Ning Yang, Kai-Di Liu, Yu-Qi Liu, Qing Fu, Wen-Juan Chen, Ya-Ping Niu, Qin Ma, Qing-Hua Zhou, Rong Yao, Xiao-Hong Zhang, Xia Cui, You-Hong Bian, Xiu-Wu Shi, Yu Ping, Yi-Fang |
author_sort | Zhou, Kai |
collection | PubMed |
description | Plastic phenotype convention between glioma stem cells (GSCs) and non-stem tumor cells (NSTCs) significantly fuels glioblastoma heterogeneity that causes therapeutic failure. Recent progressions indicate that glucose metabolic reprogramming could drive cell fates. However, the metabolic pattern of GSCs and NSTCs and its association with tumor cell phenotypes remain largely unknown. Here we found that GSCs were more glycolytic than NSTCs, and voltage-dependent anion channel 2 (VDAC2), a mitochondrial membrane protein, was critical for metabolic switching between GSCs and NSTCs to affect their phenotypes. VDAC2 was highly expressed in NSTCs relative to GSCs and coupled a glycolytic rate-limiting enzyme platelet-type of phosphofructokinase (PFKP) on mitochondrion to inhibit PFKP-mediated glycolysis required for GSC maintenance. Disruption of VDAC2 induced dedifferentiation of NSTCs to acquire GSC features, including the enhanced self-renewal, preferential expression of GSC markers, and increased tumorigenicity. Inversely, enforced expression ofVDAC2 impaired the self-renewal and highly tumorigenic properties of GSCs. PFK inhibitor clotrimazole compromised the effect of VDAC2 disruption on glycolytic reprogramming and GSC phenotypic transition. Clinically, VDAC2 expression inversely correlated with glioma grades (Immunohistochemical staining scores of VDAC2 were 4.7 ± 2.8, 3.2 ± 1.9, and 1.9 ± 1.9 for grade II, grade III, and IV, respectively, p < 0.05 for all) and the patients with high expression of VDAC2 had longer overall survival than those with low expression of VDAC2 (p = 0.0008). In conclusion, we demonstrate that VDAC2 is a new glycolytic regulator controlling the phenotype transition between glioma stem cells and non-stem cells and may serves as a new prognostic indicator and a potential therapeutic target for glioma patients. |
format | Online Article Text |
id | pubmed-6155247 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-61552472018-09-28 VDAC2 interacts with PFKP to regulate glucose metabolism and phenotypic reprogramming of glioma stem cells Zhou, Kai Yao, Yue-Liang He, Zhi-Cheng Chen, Cong Zhang, Xiao-Ning Yang, Kai-Di Liu, Yu-Qi Liu, Qing Fu, Wen-Juan Chen, Ya-Ping Niu, Qin Ma, Qing-Hua Zhou, Rong Yao, Xiao-Hong Zhang, Xia Cui, You-Hong Bian, Xiu-Wu Shi, Yu Ping, Yi-Fang Cell Death Dis Article Plastic phenotype convention between glioma stem cells (GSCs) and non-stem tumor cells (NSTCs) significantly fuels glioblastoma heterogeneity that causes therapeutic failure. Recent progressions indicate that glucose metabolic reprogramming could drive cell fates. However, the metabolic pattern of GSCs and NSTCs and its association with tumor cell phenotypes remain largely unknown. Here we found that GSCs were more glycolytic than NSTCs, and voltage-dependent anion channel 2 (VDAC2), a mitochondrial membrane protein, was critical for metabolic switching between GSCs and NSTCs to affect their phenotypes. VDAC2 was highly expressed in NSTCs relative to GSCs and coupled a glycolytic rate-limiting enzyme platelet-type of phosphofructokinase (PFKP) on mitochondrion to inhibit PFKP-mediated glycolysis required for GSC maintenance. Disruption of VDAC2 induced dedifferentiation of NSTCs to acquire GSC features, including the enhanced self-renewal, preferential expression of GSC markers, and increased tumorigenicity. Inversely, enforced expression ofVDAC2 impaired the self-renewal and highly tumorigenic properties of GSCs. PFK inhibitor clotrimazole compromised the effect of VDAC2 disruption on glycolytic reprogramming and GSC phenotypic transition. Clinically, VDAC2 expression inversely correlated with glioma grades (Immunohistochemical staining scores of VDAC2 were 4.7 ± 2.8, 3.2 ± 1.9, and 1.9 ± 1.9 for grade II, grade III, and IV, respectively, p < 0.05 for all) and the patients with high expression of VDAC2 had longer overall survival than those with low expression of VDAC2 (p = 0.0008). In conclusion, we demonstrate that VDAC2 is a new glycolytic regulator controlling the phenotype transition between glioma stem cells and non-stem cells and may serves as a new prognostic indicator and a potential therapeutic target for glioma patients. Nature Publishing Group UK 2018-09-24 /pmc/articles/PMC6155247/ /pubmed/30250190 http://dx.doi.org/10.1038/s41419-018-1015-x Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Zhou, Kai Yao, Yue-Liang He, Zhi-Cheng Chen, Cong Zhang, Xiao-Ning Yang, Kai-Di Liu, Yu-Qi Liu, Qing Fu, Wen-Juan Chen, Ya-Ping Niu, Qin Ma, Qing-Hua Zhou, Rong Yao, Xiao-Hong Zhang, Xia Cui, You-Hong Bian, Xiu-Wu Shi, Yu Ping, Yi-Fang VDAC2 interacts with PFKP to regulate glucose metabolism and phenotypic reprogramming of glioma stem cells |
title | VDAC2 interacts with PFKP to regulate glucose metabolism and phenotypic reprogramming of glioma stem cells |
title_full | VDAC2 interacts with PFKP to regulate glucose metabolism and phenotypic reprogramming of glioma stem cells |
title_fullStr | VDAC2 interacts with PFKP to regulate glucose metabolism and phenotypic reprogramming of glioma stem cells |
title_full_unstemmed | VDAC2 interacts with PFKP to regulate glucose metabolism and phenotypic reprogramming of glioma stem cells |
title_short | VDAC2 interacts with PFKP to regulate glucose metabolism and phenotypic reprogramming of glioma stem cells |
title_sort | vdac2 interacts with pfkp to regulate glucose metabolism and phenotypic reprogramming of glioma stem cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155247/ https://www.ncbi.nlm.nih.gov/pubmed/30250190 http://dx.doi.org/10.1038/s41419-018-1015-x |
work_keys_str_mv | AT zhoukai vdac2interactswithpfkptoregulateglucosemetabolismandphenotypicreprogrammingofgliomastemcells AT yaoyueliang vdac2interactswithpfkptoregulateglucosemetabolismandphenotypicreprogrammingofgliomastemcells AT hezhicheng vdac2interactswithpfkptoregulateglucosemetabolismandphenotypicreprogrammingofgliomastemcells AT chencong vdac2interactswithpfkptoregulateglucosemetabolismandphenotypicreprogrammingofgliomastemcells AT zhangxiaoning vdac2interactswithpfkptoregulateglucosemetabolismandphenotypicreprogrammingofgliomastemcells AT yangkaidi vdac2interactswithpfkptoregulateglucosemetabolismandphenotypicreprogrammingofgliomastemcells AT liuyuqi vdac2interactswithpfkptoregulateglucosemetabolismandphenotypicreprogrammingofgliomastemcells AT liuqing vdac2interactswithpfkptoregulateglucosemetabolismandphenotypicreprogrammingofgliomastemcells AT fuwenjuan vdac2interactswithpfkptoregulateglucosemetabolismandphenotypicreprogrammingofgliomastemcells AT chenyaping vdac2interactswithpfkptoregulateglucosemetabolismandphenotypicreprogrammingofgliomastemcells AT niuqin vdac2interactswithpfkptoregulateglucosemetabolismandphenotypicreprogrammingofgliomastemcells AT maqinghua vdac2interactswithpfkptoregulateglucosemetabolismandphenotypicreprogrammingofgliomastemcells AT zhourong vdac2interactswithpfkptoregulateglucosemetabolismandphenotypicreprogrammingofgliomastemcells AT yaoxiaohong vdac2interactswithpfkptoregulateglucosemetabolismandphenotypicreprogrammingofgliomastemcells AT zhangxia vdac2interactswithpfkptoregulateglucosemetabolismandphenotypicreprogrammingofgliomastemcells AT cuiyouhong vdac2interactswithpfkptoregulateglucosemetabolismandphenotypicreprogrammingofgliomastemcells AT bianxiuwu vdac2interactswithpfkptoregulateglucosemetabolismandphenotypicreprogrammingofgliomastemcells AT shiyu vdac2interactswithpfkptoregulateglucosemetabolismandphenotypicreprogrammingofgliomastemcells AT pingyifang vdac2interactswithpfkptoregulateglucosemetabolismandphenotypicreprogrammingofgliomastemcells |