Zhu Sha, Shanbhag Vinit, Wang Yanfang, Lee Jaekwon, Petris Michael
Department of Biochemistry, University of Missouri, Columbia, MO, 65211.
The Christopher S. Bond Life Science Center, University of Missouri, Columbia, MO, 65211.
J Cancer. 2017 Jul 5;8(11):1952-1958. doi: 10.7150/jca.19029. eCollection 2017.
The ATP7A protein is a ubiquitously expressed copper-translocating P-type ATPase that controls cytoplasmic copper concentrations by mediating cellular copper egress. studies have previously demonstrated that ATP7A abundance in various tumor cell lines is correlated with increased resistance to cisplatin, a widely-used chemotherapy agent. However, to date no studies have examined a role for ATP7A in tumor growth or cisplatin sensitivity . In this study, we deleted ATP7A in H-RAS transformed tumorigenic mouse embryonic fibroblasts (MEF7A-). Interestingly, loss of ATP7A was found to markedly suppress tumorigenesis in MEF7A- cells relative to wild type parental cells. This was associated with hyperaccumulation of copper and sensitivity to reactive oxygen species and hypoxia. Tumor grafts lacking ATP7A were markedly more sensitive to cisplatin chemotherapy compared to ATP7A-expressing control tumors. These findings identify ATP7A at the nexus between tumorigenesis and cisplatin resistance pathways, underscoring its potential as a therapeutic target for regulating both tumor growth and the efficacy of cisplatin treatment.
ATP7A蛋白是一种广泛表达的铜转运P型ATP酶，通过介导细胞内铜外流来控制细胞质铜浓度。此前的研究表明，各种肿瘤细胞系中ATP7A的丰度与对顺铂（一种广泛使用的化疗药物）的耐药性增加相关。然而，迄今为止，尚无研究探讨ATP7A在肿瘤生长或顺铂敏感性方面的作用。在本研究中，我们在H-RAS转化的致瘤性小鼠胚胎成纤维细胞（MEF7A-）中删除了ATP7A。有趣的是，相对于野生型亲代细胞，发现ATP7A的缺失显著抑制了MEF7A-细胞中的肿瘤发生。这与铜的过度积累以及对活性氧和缺氧的敏感性有关。与表达ATP7A的对照肿瘤相比，缺乏ATP7A的肿瘤移植物对顺铂化疗明显更敏感。这些发现确定了ATP7A处于肿瘤发生和顺铂耐药途径之间的关键位置，突出了其作为调节肿瘤生长和顺铂治疗疗效的治疗靶点的潜力。
