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ATP7B expression confers multidrug resistance through drug sequestration
F M Moinuddin1,2, Yoshinari Shinsato2,3, Masaharu Komatsu4
1Department of Neurosurgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
Oncotarget
|March 19, 2016
Summary
The ATP7B protein confers multidrug resistance (MDR) in cancer cells by enabling nuclear drug efflux and late endosomal drug sequestration. Cysteine residues in ATP7B
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- ATP7B was previously implicated in cisplatin resistance.
- ATP7A is known to confer multidrug resistance (MDR) in cancer cells.
Purpose of the Study:
- To investigate the role of ATP7B in resistance to various anticancer agents beyond cisplatin.
- To elucidate the mechanism by which ATP7B confers MDR, focusing on its metal-binding sites (MBSs) and drug sequestration.
- To identify potential therapeutic strategies to overcome ATP7B-mediated drug resistance.
Main Methods:
- Generated and utilized cancer cell lines expressing wild-type ATP7B and mutant forms (Cu0, Cu6, M6C/S).
- Assessed cellular resistance to multiple anticancer drugs, including doxorubicin, SN-38, etoposide, and paclitaxel.
- Tracked intracellular doxorubicin localization using fluorescence microscopy, observing colocalization with EGFP-ATP7B and late endosomes.
- Investigated the effect of ammonium chloride and tamoxifen on doxorubicin sequestration and drug resistance.
Main Results:
- ATP7B-expressing cells exhibited resistance to cisplatin, doxorubicin, SN-38, etoposide, and paclitaxel.
- Doxorubicin was sequestered in late endosomes in ATP7B-expressing cells, colocalizing with EGFP-ATP7B.
- Mutant ATP7B (Cu6) showed reduced resistance and impaired doxorubicin sequestration, while Cu0 and M6C/S mutants were sensitive.
- Cysteine residues in the sixth MBS of ATP7B were essential for the MDR phenotype.
- Ammonium chloride and tamoxifen reduced late endosomal doxorubicin sequestration and attenuated drug resistance.
Conclusions:
- ATP7B confers MDR to a broad spectrum of anticancer agents.
- The sixth metal-binding site of ATP7B, particularly its cysteine residues, is critical for mediating drug resistance.
- ATP7B confers MDR by promoting nuclear drug efflux and sequestering drugs in late endosomes.
- Targeting late endosomal sequestration, potentially through agents like ammonium chloride or tamoxifen, may overcome ATP7B-mediated drug resistance.
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