Hsu Wen-Jing, Hsu Ming-Chien, Chu Cheng-Ying, Lee Yu-Cheng, Yang Ching-Chieh, Liu Zei-Wei, Lee Chi-Ching, Lin Yang-Sen, Lin Cheng-Wei
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
CRISPR Gene Targeting Core Lab, Taipei Medical University, Taipei, Taiwan.
Redox Biol. 2025 Aug 26;86:103845. doi: 10.1016/j.redox.2025.103845.
Metastatic tumor cells exhibit distinct metabolic flexibility in overcoming different microenvironmental obstacles and thriving in a secondary organ; thus, metabolic vulnerabilities can potentially be targeted. It was reported that mitochondrial biogenesis and dynamics play crucial roles in disseminated tumor cells satisfying their energy demands and metabolic plasticity. However, the detailed molecular mechanism by which mitochondrial dynamics promotes tumor metastasis is still unclear. Herein, we identified that metastatic breast cancer cells exhibited increased lipid contents in mitochondria and promoted a metabolic shift towards fatty acid oxidation (FAO). The increased FAO was accompanied by promotion of mitochondrial fission. Mechanistically, we found that upregulation of DEAD-box polypeptide 3, X-linked (DDX3) promoted mitochondrial fission and facilitated FAO. Suppression of DDX3 diminished FAO and elicited mitochondrial oxidative stress in metastatic tumor cells. Moreover, DDX3 mediated dynamin-related protein 1 (DRP1) phosphorylation at S616 through collaborating with cyclin-dependent kinase 1 (CDK1). Inhibition of the DDX3-DRP1-CDK1 axis reduced cancer stemness properties and tumor metastasis. Our findings indicate that DDX3 modulates mitochondrial plasticity to drive metabolic adaptation in breast tumor metastasis. DDX3 provides a potential diagnostic biomarker and therapeutic vulnerability through which cancer metabolism can be targeted.
转移性肿瘤细胞在克服不同的微环境障碍并在次级器官中茁壮成长方面表现出独特的代谢灵活性；因此，代谢弱点有可能成为靶点。据报道，线粒体生物发生和动力学在满足播散性肿瘤细胞的能量需求和代谢可塑性方面起着关键作用。然而，线粒体动力学促进肿瘤转移的详细分子机制仍不清楚。在此，我们发现转移性乳腺癌细胞线粒体中的脂质含量增加，并促进了向脂肪酸氧化（FAO）的代谢转变。FAO的增加伴随着线粒体裂变的促进。从机制上讲，我们发现X连锁的DEAD盒多肽3（DDX3）的上调促进了线粒体裂变并促进了FAO。抑制DDX3可减少FAO并在转移性肿瘤细胞中引发线粒体氧化应激。此外，DDX3通过与细胞周期蛋白依赖性激酶1（CDK1）合作介导动力蛋白相关蛋白1（DRP1）在S616处的磷酸化。抑制DDX3-DRP1-CDK1轴可降低癌症干性特性和肿瘤转移。我们的研究结果表明，DDX3调节线粒体可塑性以驱动乳腺肿瘤转移中的代谢适应。DDX3提供了一种潜在的诊断生物标志物和治疗弱点，通过它可以靶向癌症代谢。
