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Ammonium tetrathiomolybdate treatment targets the copper transporter ATP7A and enhances sensitivity of breast cancer to cisplatin
Chisholm C.L.1; Wang H.2; Wong A.H.-H.2; Vazquez-Ortiz G.1; Chen W.1; Xu X.2; Deng C.-X.2
2016
Source PublicationOncotarget
ISSN1949-2553
Volume7Issue:51Pages:84439-84452
Abstract

Cisplatin is an effective breast cancer drug but resistance often develops over prolonged chemotherapy. Therefore, we performed a candidate approach RNAi screen in combination with cisplatin treatment to identify molecular pathways conferring survival advantages. The screen identified ATP7A as a therapeutic target. ATP7A is a copper ATPase transporter responsible for intercellular movement and sequestering of cisplatin. Pharmaceutical replacement for ATP7A by ammonium tetrathiomolybdate (TM) enhanced cisplatin treatment in breast cancer cells. Allograft and xenograft models in athymic nude mice treated with cisplatin/TM exhibited retarded tumor growth, reduced accumulation of cancer stem cells and decreased cell proliferation as compared to mono-treatment with cisplatin or TM. Cisplatin/TM treatment of cisplatinresistant tumors reduced ATP7A protein levels, attenuated cisplatin sequestering by ATP7A, increased nuclear availability of cisplatin, and subsequently enhanced DNA damage and apoptosis. Microarray analysis of gene ontology pathways that responded uniquely to cisplatin/TM double treatment depicted changes in cell cycle regulation, specifically in the G1/S transition. These findings offer the potential to combat platinum-resistant tumors and sensitize patients to conventional breast cancer treatment by identifying and targeting the resistant tumors' unique molecular adaptations.

KeywordAtp7a Breast Cancer Cisplatin Copper Resistance Sequestering
DOI10.18632/oncotarget.12992
URLView the original
Indexed BySCI
Language英语
WOS Research AreaOncology ; Cell Biology
WOS SubjectOncology ; Cell Biology
WOS IDWOS:000391353200052
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Cited Times [WOS]:16   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Co-First AuthorChisholm C.L.
Corresponding AuthorDeng C.-X.
Affiliation1.National Institute of Diabetes and Digestive and Kidney Diseases
2.Universidade de Macau
Recommended Citation
GB/T 7714
Chisholm C.L.,Wang H.,Wong A.H.-H.,et al. Ammonium tetrathiomolybdate treatment targets the copper transporter ATP7A and enhances sensitivity of breast cancer to cisplatin[J]. Oncotarget,2016,7(51):84439-84452.
APA Chisholm C.L..,Wang H..,Wong A.H.-H..,Vazquez-Ortiz G..,Chen W..,...&Deng C.-X..(2016).Ammonium tetrathiomolybdate treatment targets the copper transporter ATP7A and enhances sensitivity of breast cancer to cisplatin.Oncotarget,7(51),84439-84452.
MLA Chisholm C.L.,et al."Ammonium tetrathiomolybdate treatment targets the copper transporter ATP7A and enhances sensitivity of breast cancer to cisplatin".Oncotarget 7.51(2016):84439-84452.
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