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  3. Activation of polyamine catabolism promotes glutamine metabolism and creates a targetable vulnerability in lung cancer

Activation of polyamine catabolism promotes glutamine metabolism and creates a targetable vulnerability in lung cancer

  • Proc Natl Acad Sci U S A. 2024 Mar 26;121(13):e2319429121. doi: 10.1073/pnas.2319429121.
Xinlu Han # 1,  Deyu Wang # 1,  Liao Yang 1,  Ning Wang 2,  Jianliang Shen 3,  Jinghan Wang 1,  Lei Zhang 4,  Li Chen 5,  Shenglan Gao 1,  Wei-Xing Zong 3,  Yongbo Wang 1 6 7
Affiliations

Affiliations

  • 1 Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
  • 2 Bio-med Big Data Center, Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 3 Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, Piscataway, NJ 08854.
  • 4 Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
  • 5 Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200433, China.
  • 6 Minhang Hospital & Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
  • 7 Shanghai Key Laboratory of Medical Imaging Computing and Computer Assisted Intervention, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
  • # Contributed equally.
PMID: 38513095 DOI: 10.1073/pnas.2319429121
Abstract

Polyamines are a class of small polycationic alkylamines that play essential roles in both normal and Cancer cell growth. Polyamine metabolism is frequently dysregulated and considered a therapeutic target in Cancer. However, targeting polyamine metabolism as monotherapy often exhibits limited efficacy, and the underlying mechanisms are incompletely understood. Here we report that activation of polyamine catabolism promotes glutamine metabolism, leading to a targetable vulnerability in lung Cancer. Genetic and pharmacological activation of spermidine/spermine N1-acetyltransferase 1 (SAT1), the rate-limiting Enzyme of polyamine catabolism, enhances the conversion of glutamine to glutamate and subsequent glutathione (GSH) synthesis. This metabolic rewiring ameliorates oxidative stress to support lung Cancer cell proliferation and survival. Simultaneous glutamine limitation and SAT1 activation result in ROS accumulation, growth inhibition, and cell death. Importantly, pharmacological inhibition of either one of glutamine transport, Glutaminase, or GSH biosynthesis in combination with activation of polyamine catabolism synergistically suppresses lung Cancer cell growth and xenograft tumor formation. Together, this study unveils a previously unappreciated functional interconnection between polyamine catabolism and glutamine metabolism and establishes cotargeting strategies as potential therapeutics in lung Cancer.

Keywords

SAT1; glutamine metabolism; lung cancer; polyamine catabolism.

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