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Abstract：
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.
摘要：
代谢重编程是癌症的标志，使癌细胞迅速增殖，入侵,和转移。我们表明，转移性乳腺癌细胞系和继发性转移性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在原发性肿瘤中高表达并促进细胞活力，它在转移中下调。我们进一步表明，CKMT1下调，如在乳腺癌转移中所见，提高线粒体活性氧（ROS）水平。CKMT1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能，这可以通过抗氧化处理逆转。因此，我们的研究调和了关于代谢产物在肌酸代谢途径在乳腺癌进展中的作用的相互矛盾的证据，CKMT1表达的上下文依赖性调节促进细胞活力，细胞迁移，和细胞入侵，这是转移性扩散的标志。
