α-Ketoglutarate-Activated NF-κB Signaling Promotes Compensatory Glucose Uptake and Brain Tumor Development

Xiongjun Wang; Ruilong Liu; Xiujuan Qu; Hua Yu; Huiying Chu; Yajuan Zhang; Wencheng Zhu; Xueyuan Wu; Hong Gao; Bangbao Tao; Wenfeng Li; Ji Liang; Guohui Li; Weiwei Yang

doi:10.1016/j.molcel.2019.07.007

α-Ketoglutarate-Activated NF-κB Signaling Promotes Compensatory Glucose Uptake and Brain Tumor Development

Mol Cell. 2019 Oct 3;76(1):148-162.e7. doi: 10.1016/j.molcel.2019.07.007. Epub 2019 Aug 22.

Authors

Xiongjun Wang¹, Ruilong Liu², Xiujuan Qu³, Hua Yu², Huiying Chu⁴, Yajuan Zhang², Wencheng Zhu⁵, Xueyuan Wu⁶, Hong Gao², Bangbao Tao⁷, Wenfeng Li⁶, Ji Liang², Guohui Li⁸, Weiwei Yang⁹

Affiliations

¹ State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou 510006, China.
² State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
³ Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China.
⁴ Laboratory of Molecular Modeling, State Key Lab of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
⁵ State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
⁶ Department of Radiation Oncology, First Affiliated Hospital of Wenzhou Medical College, Wenzhou, Zhejiang 325000, China.
⁷ Department of Neurosurgery, XinHua Hospital School of Medicine, Shanghai Jiaotong University, Shanghai 200092, China.
⁸ Laboratory of Molecular Modeling, State Key Lab of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China. Electronic address: ghli@dicp.ac.cn.
⁹ State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: wyang@sibcb.ac.cn.

PMID: 31447391
DOI: 10.1016/j.molcel.2019.07.007

Abstract

The rapid proliferation of cancer cells and dysregulated vasculature within the tumor leads to limited nutrient accessibility. Cancer cells often rewire their metabolic pathways for adaption to nutrient stress, and the underlying mechanism remains largely unknown. Glutamate dehydrogenase 1 (GDH1) is a key enzyme in glutaminolysis that converts glutamate to α-ketoglutarate (α-KG). Here, we show that, under low glucose, GDH1 is phosphorylated at serine (S) 384 and interacts with RelA and IKKβ. GDH1-produced α-KG directly binds to and activates IKKβ and nuclear factor κB (NF-κB) signaling, which promotes glucose uptake and tumor cell survival by upregulating GLUT1, thereby accelerating gliomagenesis. In addition, GDH1 S384 phosphorylation correlates with the malignancy and prognosis of human glioblastoma. Our finding reveals a unique role of α-KG to directly regulate signal pathway, uncovers a distinct mechanism of metabolite-mediated NF-κB activation, and also establishes the critical role of α-KG-activated NF-κB in brain tumor development.

Keywords: GDH1; NF-κB; glucose deficiency; tumorigenesis; α-ketoglutarate.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Aged
Aged, 80 and over
Animals
Brain Neoplasms / genetics
Brain Neoplasms / metabolism*
Brain Neoplasms / pathology
Cell Line, Tumor
Cell Proliferation*
Cell Survival
Child
Energy Metabolism*
Female
Gene Expression Regulation, Neoplastic
Glioblastoma / genetics
Glioblastoma / metabolism*
Glioblastoma / pathology
Glucose / deficiency
Glucose / metabolism*
Glucose Transporter Type 1 / genetics
Glucose Transporter Type 1 / metabolism
Glutamate Dehydrogenase / genetics
Glutamate Dehydrogenase / metabolism*
HEK293 Cells
Humans
I-kappa B Kinase / genetics
I-kappa B Kinase / metabolism
Ketoglutaric Acids / metabolism*
Male
Mice, Inbred BALB C
Mice, Nude
Middle Aged
NF-kappa B / genetics
NF-kappa B / metabolism*
Neoplasm Grading
Phosphorylation
Signal Transduction
Transcription Factor RelA / genetics
Transcription Factor RelA / metabolism
Young Adult

Substances

Glucose Transporter Type 1
Ketoglutaric Acids
NF-kappa B
RELA protein, human
SLC2A1 protein, human
Transcription Factor RelA
Glutamate Dehydrogenase
GLUD1 protein, human
I-kappa B Kinase
IKBKB protein, human
Glucose