Johns Hopkins University In Vivo Cellular and Molecular Imaging Center, Division of Cancer Imaging Research, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Johns Hopkins University In Vivo Cellular and Molecular Imaging Center, Division of Cancer Imaging Research, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Medical Laboratory, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Cell Rep. 2024 Apr 23;43(4):114121. doi: 10.1016/j.celrep.2024.114121. Epub 2024 Apr 12.
Metabolic reprogramming is a hallmark of cancer, enabling cancer cells to rapidly proliferate, invade, and metastasize. We show that creatine levels in metastatic breast cancer cell lines and secondary metastatic tumors are driven by the ubiquitous mitochondrial creatine kinase (CKMT1). We discover that, while CKMT1 is highly expressed in primary tumors and promotes cell viability, it is downregulated in metastasis. We further show that CKMT1 downregulation, as seen in breast cancer metastasis, drives up mitochondrial reactive oxygen species (ROS) levels. CKMT1 downregulation contributes to the migratory and invasive potential of cells by ROS-induced upregulation of adhesion and degradative factors, which can be reversed by antioxidant treatment. Our study thus reconciles conflicting evidence about the roles of metabolites in the creatine metabolic pathway in breast cancer progression and reveals that tight, context-dependent regulation of CKMT1 expression facilitates cell viability, cell migration, and cell invasion, which are hallmarks of metastatic spread.
代谢重编程是癌症的一个标志，使癌细胞能够快速增殖、侵袭和转移。我们表明，转移性乳腺癌细胞系和继发性转移肿瘤中的肌酸水平是由普遍存在的线粒体肌酸激酶（CKMT1）驱动的。我们发现，虽然 CKMT1 在原发性肿瘤中高度表达并促进细胞活力，但在转移中它被下调。我们进一步表明，乳腺癌转移中所见的 CKMT1 下调会导致线粒体活性氧（ROS）水平升高。CKMT1 的下调通过 ROS 诱导的粘附和降解因子的上调促进细胞的迁移和侵袭潜力，这可以通过抗氧化剂治疗来逆转。因此，我们的研究调和了关于肌酸代谢途径中的代谢物在乳腺癌进展中的作用的相互矛盾的证据，并揭示了 CKMT1 表达的紧密、上下文相关的调节促进了细胞活力、细胞迁移和细胞侵袭，这些都是转移扩散的标志。
