The objectives of our studies are to elucidate the biological roles of the ATP7A copper transporter in the nutritional and metabolic processes of tumor growth and resistance against cisplatin chemotherapy. A hallmark of cancer cells is an underlying deviation in nutrient metabolism, a feature that permits efficient incorporation of nutrients to support abnormal proliferation and metastasis. Understanding the pathways of nutrient transport that are rate limiting for tumor growth and metastasis is increasingly recognized as critical in the development of enzyme inhibitors that will preferentially kill tumor cells. Copper is an essential trace element that plays a fundamental role in the biochemistry of all aerobic organisms. The inherited disorder of copper metabolism, Menkes disease, has revealed the importance of the affected protein ATP7A in cellular copper homeostasis. ATP7A functions not only as an exporter of copper, thus preventing cellular copper toxicity, but also in the delivery of copper to critical enzymes in the secretory pathway. A group of secreted enzymes that are thought to rely on ATP7A for their copper cofactor include the lysyl oxidase family of proteins (LOX and LOXL1-4). These proteins play key roles in tumor growth and metastasis, highlighting a unique connection between copper homeostasis and cancer, and underscoring a priori the potential to inhibit ATP7A as a means to prevent LOX-mediated pathways in cancer. Furthermore, studies suggest that the ATP7A copper transporter is also important in protecting cells against cisplatin, a chemotherapy agent used to treat a wide variety of cancers. Thus, we propose that ATP7A could be exploited as a target in cancer treatment not only to prevent tumor growth, but also to potentiate cisplatin chemotherapy. In support of this hypothesis, our preliminary results demonstrate that tumorigenesis of RAS-transformed fibroblasts was inhibited by deletion of the ATP7A gene, which also rendered these cells hypersensitive to cisplatin chemotherapy. Additionally, RNAi-mediated silencing of ATP7A in the 4T1 cell model of orthotopic breast carcinoma blocked primary tumor growth and markedly inhibited secondary lung metastasis. The studies outlined in the current proposal seek to elucidate the roles of ATP7A in both cancer growth and chemotherapy drug resistance, and thus its potential as a therapeutic target.

Public Health Relevance

Recent studies have recognized the critical requirement for copper in tumor growth, and the requirement for copper transporters in resistance to platinum-based chemotherapy agents. This work seeks to identify and understand specific mechanisms of copper homeostasis in cancer cells that might ultimately be exploited to prevent tumorigenesis and enhance the efficacy of chemotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA190265-05
Application #
9603706
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Kondapaka, Sudhir B
Project Start
2014-12-01
Project End
2019-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Missouri-Columbia
Department
Biochemistry
Type
Schools of Medicine
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
Zhu, Sha; Shanbhag, Vinit; Wang, Yanfang et al. (2017) A Role for The ATP7A Copper Transporter in Tumorigenesis and Cisplatin Resistance. J Cancer 8:1952-1958
Zhu, Sha; Shanbhag, Vinit; Hodgkinson, Victoria L et al. (2016) Multiple di-leucines in the ATP7A copper transporter are required for retrograde trafficking to the trans-Golgi network. Metallomics 8:993-1001