한빛사논문
- 조회587
동아대학교
Hye Jin Yun1†, Min Li2†, Dong Guo2†, So Mi Jeon1, Su Hwan Park1, Je Sun Lim1, Su Bin Lee1, Rui Liu4, Linyong Du5, Seok‑Ho Kim1, Tae Hwan Shin6, Seong‑il Eyun7, Yun‑Yong Park7*, Zhimin Lu2,3* and Jong‑Ho Lee1,6*
1Department of Health Sciences, The Graduate School of Dong-A University, Busan 49315, Republic of Korea.
2Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Afliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China.
3Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China.
4State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, People’s Republic of China.
5Key Laboratory of Laboratory of Medicine, Ministry of Education of China, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang 325000, People’s Republic of China.
6Department of Biomedical Sciences, Dong-A University, Busan 49315, Republic of Korea.
7Department of Life Science, Chung-Ang University, Seoul 06974, Republic of Korea.
†Hye Jin Yun, Min Li and Dong Guo contributed equally to this work.
*Correspondence: Yun‑Yong Park, Zhimin Lu, Jong‑Ho Lee
Abstract
Background: Cancer cells undergo cellular adaptation through metabolic reprogramming to sustain survival and rapid growth under various stress conditions. However, how brain tumors modulate their metabolic flexibility in the naturally serine/glycine (S/G)-deficient brain microenvironment remain unknown.
Methods: We used a range of primary/stem-like and established glioblastoma (GBM) cell models in vitro and in vivo. To identify the regulatory mechanisms of S/G deprivation-induced metabolic flexibility, we employed high-throughput RNA-sequencing, transcriptomic analysis, metabolic flux analysis, metabolites analysis, chromatin immunoprecipitation (ChIP), luciferase reporter, nuclear fractionation, cycloheximide-chase, and glucose consumption. The clinical significances were analyzed in the genomic database (GSE4290) and in human GBM specimens.
Results: The high-throughput RNA-sequencing and transcriptomic analysis demonstrate that the de novo serine synthesis pathway (SSP) and glycolysis are highly activated in GBM cells under S/G deprivation conditions. Mechanistically, S/G deprivation rapidly induces reactive oxygen species (ROS)-mediated AMP-activated protein kinase (AMPK) activation and AMPK-dependent hypoxia-inducible factor (HIF)-1α stabilization and transactivation. Activated HIF-1α in turn promotes the expression of SSP enzymes phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH). In addition, the HIF-1α-induced expression of glycolytic genes (GLUT1, GLUT3, HK2, and PFKFB2) promotes glucose uptake, glycolysis, and glycolytic flux to fuel SSP, leading to elevated de novo serine and glycine biosynthesis, NADPH/NADP+ ratio, and the proliferation and survival of GBM cells. Analyses of human GBM specimens reveal that the levels of overexpressed PHGDH, PSAT1, and PSPH are positively correlated with levels of AMPK T172 phosphorylation and HIF-1α expression and the poor prognosis of GBM patients.
Conclusion: Our findings reveal that metabolic stress-enhanced glucose-derived de novo serine biosynthesis is a critical metabolic feature of GBM cells, and highlight the potential to target SSP for treating human GBM.
논문정보
- Research article
- 2023년 12월 (BRIC 등록일 2023-12-18)
- 국내(교신)+국외 연구진
- 생명과학 > 노화/암생물학
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