2. Academic Validation
  3. The proto-oncogene tyrosine kinase c-SRC facilitates glioblastoma progression by remodeling fatty acid synthesis

The proto-oncogene tyrosine kinase c-SRC facilitates glioblastoma progression by remodeling fatty acid synthesis

  • Nat Commun. 2024 Aug 28;15(1):7455. doi: 10.1038/s41467-024-51444-0.
Wentao Zhao # 1 2,  Cong Ouyang # 3,  Liang Zhang # 4,  Jinyang Wang # 3,  Jiaojiao Zhang # 3,  Yan Zhang 3,  Chen Huang 3,  Qiao Xiao 3,  Bin Jiang 3,  Furong Lin 3,  Cixiong Zhang 3,  Mingxia Zhu 3,  Changchuan Xie 3,  Xi Huang 3,  Bingchang Zhang 4,  Wenpeng Zhao 4,  Jiawei He 4,  Sifang Chen 4,  Xiyao Liu 4,  Donghai Lin 5,  Qinxi Li 6,  Zhanxiang Wang 7
Affiliations

Affiliations

  • 1 Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China. zhaowentao@xmu.edu.cn.
  • 2 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China. zhaowentao@xmu.edu.cn.
  • 3 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China.
  • 4 Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
  • 5 MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, Key Laboratory of Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, China.
  • 6 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China. liqinxi@xmu.edu.cn.
  • 7 Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China. wangzx@xmu.edu.cn.
  • # Contributed equally.
PMID: 39198451 DOI: 10.1038/s41467-024-51444-0
Abstract

Increased fatty acid synthesis benefits glioblastoma malignancy. However, the coordinated regulation of cytosolic acetyl-CoA production, the exclusive substrate for fatty acid synthesis, remains unclear. Here, we show that proto-oncogene tyrosine kinase c-SRC is activated in glioblastoma and remodels cytosolic acetyl-CoA production for fatty acid synthesis. Firstly, acetate is an important substrate for fatty acid synthesis in glioblastoma. c-SRC phosphorylates acetyl-CoA synthetase ACSS2 at Tyr530 and Tyr562 to stimulate the conversion of acetate to acetyl-CoA in cytosol. Secondly, c-SRC inhibits citrate-derived acetyl-CoA synthesis by phosphorylating ATP-citrate lyase ACLY at Tyr682. ACLY phosphorylation shunts citrate to IDH1-catalyzed NADPH production to provide reducing equivalent for fatty acid synthesis. The c-SRC-unresponsive double-mutation of ACSS2 and ACLY significantly reduces fatty acid synthesis and hampers glioblastoma progression. In conclusion, this remodeling fulfills the dual needs of glioblastoma cells for both acetyl-CoA and NADPH in fatty acid synthesis and provides evidence for glioma treatment by c-SRC inhibition.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-13805
    99.35%, Src抑制剂
    Src
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