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ATP7B expression confers multidrug resistance through drug sequestration

We previously reported that ATP7B is involved in cisplatin resistance and ATP7A confers multidrug resistance (MDR) in cancer cells. In this study, we show that ATP7B expressing cells also are resistant to doxorubicin, SN-38, etoposide, and paclitaxel as well as cisplatin. In ATP7B expressing cells,...

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Autores principales: Moinuddin, F M, Shinsato, Yoshinari, Komatsu, Masaharu, Mitsuo, Ryoichi, Minami, Kentaro, Yamamoto, Masatatsu, Kawahara, Kohich, Hirano, Hirofumi, Arita, Kazunori, Furukawa, Tatsuhiko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008400/
https://www.ncbi.nlm.nih.gov/pubmed/26988911
http://dx.doi.org/10.18632/oncotarget.8059
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author Moinuddin, F M
Shinsato, Yoshinari
Komatsu, Masaharu
Mitsuo, Ryoichi
Minami, Kentaro
Yamamoto, Masatatsu
Kawahara, Kohich
Hirano, Hirofumi
Arita, Kazunori
Furukawa, Tatsuhiko
author_facet Moinuddin, F M
Shinsato, Yoshinari
Komatsu, Masaharu
Mitsuo, Ryoichi
Minami, Kentaro
Yamamoto, Masatatsu
Kawahara, Kohich
Hirano, Hirofumi
Arita, Kazunori
Furukawa, Tatsuhiko
author_sort Moinuddin, F M
collection PubMed
description We previously reported that ATP7B is involved in cisplatin resistance and ATP7A confers multidrug resistance (MDR) in cancer cells. In this study, we show that ATP7B expressing cells also are resistant to doxorubicin, SN-38, etoposide, and paclitaxel as well as cisplatin. In ATP7B expressing cells, doxorubicin relocated from the nuclei to the late-endosome at 4 hours after doxorubicin exposure. EGFP-ATP7B mainly colocalized with doxorubicin. ATP7B has six metal binding sites (MBSs) in the N-terminal cytoplasmic region. To investigate the role of the MBSs of ATP7B in doxorubicin resistance, we used three mutant ATP7B (Cu0, Cu6 and M6C/S) expressing cells. Cu0 has no MBSs, Cu6 has only the sixth MBS and M6C/S carries CXXC to SXXS mutation in the sixth MBS. Cu6 expressing cells were less resistance to the anticancer agents than wild type ATP7B expressing cells, and had doxorubicin sequestration in the late-endosome. Cu0- and M6C/S-expressing cells were sensitive to doxorubicin. In these cells, doxorubicin did not relocalize to the late-endosome. EGFP-M6C/S mainly localized to the trans-Golgi network (TGN) even in the presence of copper. Thus the cysteine residues in the sixth MBS of ATP7B are essential for MDR phenotype. Finally, we found that ammonium chloride and tamoxifen suppressed late endosomal sequestration of doxorubicin, thereby attenuating drug resistance. These results suggest that the sequestration depends on the acidity of the vesicles partly. We here demonstrate that ATP7B confers MDR by facilitating nuclear drug efflux and late endosomal drug sequestration.
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spelling pubmed-50084002016-09-12 ATP7B expression confers multidrug resistance through drug sequestration Moinuddin, F M Shinsato, Yoshinari Komatsu, Masaharu Mitsuo, Ryoichi Minami, Kentaro Yamamoto, Masatatsu Kawahara, Kohich Hirano, Hirofumi Arita, Kazunori Furukawa, Tatsuhiko Oncotarget Research Paper We previously reported that ATP7B is involved in cisplatin resistance and ATP7A confers multidrug resistance (MDR) in cancer cells. In this study, we show that ATP7B expressing cells also are resistant to doxorubicin, SN-38, etoposide, and paclitaxel as well as cisplatin. In ATP7B expressing cells, doxorubicin relocated from the nuclei to the late-endosome at 4 hours after doxorubicin exposure. EGFP-ATP7B mainly colocalized with doxorubicin. ATP7B has six metal binding sites (MBSs) in the N-terminal cytoplasmic region. To investigate the role of the MBSs of ATP7B in doxorubicin resistance, we used three mutant ATP7B (Cu0, Cu6 and M6C/S) expressing cells. Cu0 has no MBSs, Cu6 has only the sixth MBS and M6C/S carries CXXC to SXXS mutation in the sixth MBS. Cu6 expressing cells were less resistance to the anticancer agents than wild type ATP7B expressing cells, and had doxorubicin sequestration in the late-endosome. Cu0- and M6C/S-expressing cells were sensitive to doxorubicin. In these cells, doxorubicin did not relocalize to the late-endosome. EGFP-M6C/S mainly localized to the trans-Golgi network (TGN) even in the presence of copper. Thus the cysteine residues in the sixth MBS of ATP7B are essential for MDR phenotype. Finally, we found that ammonium chloride and tamoxifen suppressed late endosomal sequestration of doxorubicin, thereby attenuating drug resistance. These results suggest that the sequestration depends on the acidity of the vesicles partly. We here demonstrate that ATP7B confers MDR by facilitating nuclear drug efflux and late endosomal drug sequestration. Impact Journals LLC 2016-03-14 /pmc/articles/PMC5008400/ /pubmed/26988911 http://dx.doi.org/10.18632/oncotarget.8059 Text en Copyright: © 2016 Moinuddin et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Moinuddin, F M
Shinsato, Yoshinari
Komatsu, Masaharu
Mitsuo, Ryoichi
Minami, Kentaro
Yamamoto, Masatatsu
Kawahara, Kohich
Hirano, Hirofumi
Arita, Kazunori
Furukawa, Tatsuhiko
ATP7B expression confers multidrug resistance through drug sequestration
title ATP7B expression confers multidrug resistance through drug sequestration
title_full ATP7B expression confers multidrug resistance through drug sequestration
title_fullStr ATP7B expression confers multidrug resistance through drug sequestration
title_full_unstemmed ATP7B expression confers multidrug resistance through drug sequestration
title_short ATP7B expression confers multidrug resistance through drug sequestration
title_sort atp7b expression confers multidrug resistance through drug sequestration
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008400/
https://www.ncbi.nlm.nih.gov/pubmed/26988911
http://dx.doi.org/10.18632/oncotarget.8059
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