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ATP7A Delivers Copper to the Lysyl Oxidase Family of Enzymes and Promotes Tumorigenesis and Metastasis

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ATP7A Delivers Copper to the Lysyl Oxidase Family of Enzymes and Promotes Tumorigenesis and Metastasis ATP7A delivers copper to the lysyl oxidase family of enzymes and promotes tumorigenesis and metastasis Vinit Shanbhaga,b, Kimberly Jasmer-McDonalda,b, Sha Zhua,b, Adam L. Martina,b, Nikita Gudekarb,c, Aslam Khana,b, Erik Ladomerskya,b, Kamlendra Singhb, Gary A. Weismana,b, and Michael J. Petrisa,b,c,d,1 aDepartment of Biochemistry, University of Missouri, Columbia, MO 65211; bThe Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65211; cGenetics Area Program, University of Missouri, Columbia, MO 65211; and dDepartment of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO 65211 Edited by Mary Lou Guerinot, Dartmouth College, Hanover, NH, and approved February 25, 2019 (received for review October 11, 2018) Lysyl oxidase (LOX) and LOX-like (LOXL) proteins are copper- inhibiting copper incorporation into these enzymes may be an dependent metalloenzymes with well-documented roles in tumor effective strategy to inhibit LOX-dependent metastasis. How- metastasis and fibrotic diseases. The mechanism by which copper ever, the mechanism of copper incorporation into LOX and is delivered to these enzymes is poorly understood. In this study, LOXL proteins is poorly understood. The copper-binding cata- we demonstrate that the copper transporter ATP7A is necessary lytic domain of each LOX family member is lumenally oriented for the activity of LOX and LOXL enzymes. Silencing of ATP7A (extracytoplasmic), suggesting that copper insertion occurs via a inhibited LOX activity in the 4T1 mammary carcinoma cell line, conserved mechanism during the biosynthesis of these enzymes resulting in a loss of LOX-dependent mechanisms of metastasis, en route through the secretory pathway. Previous studies have including the phosphorylation of focal adhesion kinase and myeloid shown that the Golgi-localized copper transporter ATP7A de- cell recruitment to the lungs, in an orthotopic mouse model of livers copper to tyrosinase, a metalloenzyme with an extrac- ytoplasmic copper-binding catalytic domain (24). In addition, breast cancer. ATP7A silencing was also found to attenuate LOX LOX activity is reduced in Menkes disease fibroblasts, which activity and metastasis of Lewis lung carcinoma cells in mice. Meta- contain mutations in the ATP7A gene (25). However, the extent analysis of breast cancer patients found that high ATP7A expression to which ATP7A is required for the activity of different members was significantly correlated with reduced survival. Taken together, of the LOX family of enzymes and, by extension, the importance these results identify ATP7A as a therapeutic target for blocking of ATP7A in LOX-mediated pathologies remain unknown. CELL BIOLOGY LOX- and LOXL-dependent malignancies. Here we demonstrate that ATP7A is required for the activity of multiple members of the LOX family, and that silencing breast cancer | lung cancer | copper | lysyl oxidase | metastasis ATP7A in two different cancer cell lines suppresses tumorigen- esis and metastasis in mice. Importantly, elevated ATP7A ex- opper is an essential micronutrient required as a catalytic pression was found to be significantly correlated with reduced Ccofactor for several metalloenzymes, including those involved survival in breast cancer patients, suggesting a role for ATP7A in in cancer-promoting activities (1). Copper-dependent enzymes human cancer. These studies identify ATP7A as a target for with roles in tumor growth or metastasis include mitogen-activated inhibiting LOX-dependent malignancies. c kinase 1 (2, 3), superoxide dismutase 1 (4), cytochrome oxidase Results (5), and members of lysyl oxidase (LOX) family (6–8). The dis- covery that copper concentrations in serum and tumors are ele- ATP7A Is Necessary and Sufficient for Copper-Dependent Activity of vated in cancer patients and are correlated with disease severity LOX Family Members. The 4T1 cells were chosen as a model of metastatic human breast cancer because when orthotopically has prompted speculation that copper delivery to oncogenic en- – implanted into the mammary glands of mice, these cells readily zymes may be rate-limiting for tumor growth and metastasis (9 metastasize to the lung in a LOX-dependent manner (7, 23, 26). 11). This idea has been supported by reports that copper chelation reduces tumor growth and malignancy in animal models of cancer Significance (12, 13). Clinical studies indicate that copper chelation prolongs the survival of patients with late-stage breast cancer (14) and kidney cancer (15). These studies raise the possibility that blocking The family of copper-dependent lysyl oxidase (LOX) enzymes specific steps in the delivery of copper to oncogenic metalloenzymes contributes to tumor metastasis. In this study, we show that may provide an approach to treating cancer. the ATP7A copper transporter is required to deliver copper to LOX is a secreted copper-dependent amine oxidase that plays LOX family members. Deletion of ATP7A inhibited LOX activity critical roles in the development of connective tissue and in breast and lung cancer cell lines, resulting in a significant loss remodeling of the extracellular matrix by catalyzing the cross- of tumor growth and metastatic potential of these cells in mice. linking of collagen and elastin (16). In addition to LOX, several Elevated expression of ATP7A was found to be associated with LOX-like enzymes (LOXL1–4) have been identified that share a reduced survival of breast cancer patients. Our study suggests conserved catalytic copper-binding domain. To date, functional that blocking the function of ATP7A could be an approach to roles for LOX or LOXL enzymes have been documented in inhibiting LOX-dependent malignancies. breast, colorectal, prostate, gastric, hepatic, pancreatic, and head and neck cancers, as well as in cancers of the skin, including Author contributions: V.S., K.J.-M., S.Z., G.A.W., and M.J.P. designed research; V.S., melanoma (6, 17–19). LOX has been shown to promote tumor K.J.-M., S.Z., A.L.M., N.G., A.K., and E.L. performed research; V.S., K.J.-M., S.Z., A.L.M., N.G., A.K., E.L., K.S., G.A.W., and M.J.P. analyzed data; and V.S. and M.J.P. wrote cell migration and adhesion via the activation of focal adhesion the paper. kinase (FAK1) (20–22). In addition, LOX and LOXL2 activity is required to facilitate the recruitment of myeloid cells to meta- The authors declare no conflict of interest. static sites, creating a favorable environment for the subsequent This article is a PNAS Direct Submission. invasion and growth of tumor cells (18, 19, 23). Published under the PNAS license. The importance of LOX and LOXL proteins in cancer has led 1To whom correspondence should be addressed. Email: [email protected]. to intensive efforts to develop inhibitors of these enzymes as This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. potential anticancer therapies. Since all LOX family members 1073/pnas.1817473116/-/DCSupplemental. share a functional requirement for copper, we surmised that www.pnas.org/cgi/doi/10.1073/pnas.1817473116 PNAS Latest Articles | 1of6 Downloaded by guest on September 24, 2021 We found that all known LOX family members were expressed overlapped with antibodies against the Golgi marker protein, in 4T1 cells under standard culture conditions (SI Appendix, Fig. GM130 (SI Appendix,Fig.S2A). As expected, ATP7A was not S1A), and that 4T1 tumors grown orthotopically in the mammary detected in C3/ATP7A− and C8/ATP7A− cells by immunofluo- fat pads of BALB/c mice expressed significantly higher levels of rescence microscopy (Fig. 1B). Consistent with the known role Lox, Loxl2, Loxl3, and Loxl4 mRNAs relative to the adjacent of ATP7A in copper export (28), copper concentrations were stromal tissue (SI Appendix, Fig. S1B). elevated in C3/ATP7A− and C8/ATP7A− cells compared with To investigate the requirement for ATP7A in LOX activity, we 4T1-WT cells (SI Appendix,Fig.S2B). However, the growth rates silenced Atp7a gene expression in murine 4T1 breast carcinoma of C3/ATP7A− and C8/ATP7A− cells were not significantly dif- cells using a CRISPR-Cas9 approach. Immunoblot analysis ferent from the growth rate of 4T1-WT cells (SI Appendix, Fig. C confirmed the absence of ATP7A protein in two independent S2 ), suggesting that the elevated copper concentrations were CRISPR clones, C3/ATP7A− and C8/ATP7A− (Fig. 1A). We not cytotoxic. LOX activity was detected in the conditioned media of 4T1-WT cells and was diminished by pretreating these cells used immunofluorescence microscopy to verify that ATP7A was β localized to the Golgi apparatus in wild-type 4T1 cells (4T1- with -aminopropionitrile (BAPN), a specific inhibitor of the LOX family of enzymes (29) (Fig. 1C). In contrast, LOX activity WT), a site where ATP7A is thought to metallate nascent − metalloenzymes within the secretory pathway (24, 27). ATP7A was was virtually undetectable in the media of both C3/ATP7A and C8/ATP7A− cells (Fig. 1C), suggesting that LOX activity is de- localized to the perinuclear region in 4T1-WT cells (Fig. 1B), which pendent on ATP7A expression. These observations were not due to off-target effects of CRISPR- Cas9, because reduced LOX activity was also observed in 4T1 cells in which ATP7A was silenced using an RNAi approach (SI Ap- pendix,Fig.S3A and B). Furthermore, LOX activity was restored to wild-type levels in C3/ATP7A− cells transfected with a human ATP7A expression plasmid (Fig. 1D). LOX activity in C3/ATP7A− cells could be restored by the addition of supraphysiological copper concentrations to the culture medium (Fig. 1E). These observa- tions suggest that the reduction in LOX activity in the absence of ATP7A is due to a disruption of copper delivery to LOX. While these data support the hypothesis that ATP7A mediates copper delivery to LOX, a potential caveat to this conclusion is that commercial LOX assays, like the one used in our study, do not distinguish between the activities of different LOX family members.
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