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

• DOI: 10.1073/pnas.2319429121
• Publication Date: 2024-03-21T18:49:24Z
• Authors: Xinlu Han; Deyu Wang; Liao Yang; Ning Wang; Jianliang Shen; Jinghan Wang; Lei Zhang; Li Chen; Shenglan Gao; Wei-Xing Zong; Yongbo Wang
• Keywords: Polyamine; Catabolism; Glutaminase

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