论文
您当前的位置 :
Activation of polyamine catabolism promotes glutamine metabolism and creates a targetable vulnerability in lung cancer
论文作者 Han, XL; Wang, DY; Yang, L; Wang, N; Shen, JL; Wang, JH; Zhang, L; Chen, L; Gao, SL; Zong, WX; Wang, YB
期刊/会议名称 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
论文年度 2024
论文类别
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.

13
121
影响因子 9.4