J Cancer 2017; 8(11):1952-1958. doi:10.7150/jca.19029

Research Paper

A Role for The ATP7A Copper Transporter in Tumorigenesis and Cisplatin Resistance

Sha Zhu1,3,*, Vinit Shanbhag1,3,*, Yanfang Wang2,3, Jaekwon Lee4, Michael Petris1,2,3,✉

1. Department of Biochemistry, University of Missouri, Columbia, MO, 65211
2. Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, 65211
3. The Christopher S. Bond Life Science Center, University of Missouri, Columbia, MO, 65211
4. Redox Biology Center, Department of Biochemistry, University of Nebraska, Lincoln, Nebraska, 68588
*These authors contributed equally to this study.

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Zhu S, Shanbhag V, Wang Y, Lee J, Petris M. A Role for The ATP7A Copper Transporter in Tumorigenesis and Cisplatin Resistance. J Cancer 2017; 8(11):1952-1958. doi:10.7150/jca.19029. Available from http://www.jcancer.org/v08p1952.htm

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The ATP7A protein is a ubiquitously expressed copper-translocating P-type ATPase that controls cytoplasmic copper concentrations by mediating cellular copper egress. In vitro 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 vivo. In this study, we deleted ATP7A in H-RAS transformed tumorigenic mouse embryonic fibroblasts (MEFRAS7A-). Interestingly, loss of ATP7A was found to markedly suppress tumorigenesis in MEFRAS7A- 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.

Keywords: ATP7A, Copper transporter, Cisplatin resistance, Tumorigenesis