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

• 成果类型: Article
• 署名作者: Han, Xinlu; Wang, Deyu; Yang, Liao; Wang, Ning; Shen, Jianliang; Wang, Jinghan; Zhang, Lei; Chen, Li; Gao, Shenglan; Zong, Wei-Xing; Wang, Yongbo
• 署名单位: Fudan University; Chinese Academy of Sciences; Shanghai Institute of Nutrition & Health, CAS; University of Chinese Academy of Sciences, CAS; Rutgers University System; Rutgers University New Brunswick; Fudan University; Fudan University; Fudan University; Fudan University; Fudan University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10044
• DOI: 10.1073/pnas.2319429121
• 发表日期: 2024-03-26
• 关键词: spermidine spermine n1-acetyltransferase; oxidase; translation; induction; depletion; efficacy; GROWTH; inhibition; resistance; therapies

摘要

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.