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ID 56955
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Kobuchi, Hirotsugu 1 Department of Cell Chemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Moriya, Koko Applied Molecular Bioscience, Graduate School of Medicine, Yamaguchi University
Ogino, Tetsuya Department of Nursing Science, Faculty of Health and Welfare Science, Okayama Prefectural University
Fujita, Hirofumi Department of Cytology and Histology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science
Inoue, Keiji Department of Urology, Kochi Medical School
Shuin, Taro Department of Urology, Kochi Medical School
Yasuda, Tatsuji 1 Department of Cell Chemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Utsumi, Kozo Department of Cytology and Histology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science
Utsumi, Toshihiko Applied Molecular Bioscience, Graduate School of Medicine, Yamaguchi University
Abstract
Accumulation of protoporphyrin IX (PpIX) in malignant cells is the basis of 5-aminolevulinic acid (ALA)-mediated photodynamic therapy. We studied the expression of proteins that possibly affect ALA-mediated PpIX accumulation, namely oligopeptide transporter-1 and -2, ferrochelatase and ATP-binding cassette transporter G2 (ABCG2), in several tumor cell lines. Among these proteins, only ABCG2 correlated negatively with ALA-mediated PpIX accumulation. Both a subcellular fractionation study and confocal laser microscopic analysis revealed that ABCG2 was distributed not only in the plasma membrane but also intracellular organelles, including mitochondria. In addition, mitochondrial ABCG2 regulated the content of ALA-mediated PpIX in mitochondria, and Ko143, a specific inhibitor of ABCG2, enhanced mitochondrial PpIX accumulation. To clarify the possible roles of mitochondrial ABCG2, we characterized stably transfected-HEK (ST-HEK) cells overexpressing ABCG2. In these ST-HEK cells, functionally active ABCG2 was detected in mitochondria, and treatment with Ko143 increased ALA-mediated mitochondrial PpIX accumulation. Moreover, the mitochondria isolated from ST-HEK cells exported doxorubicin probably through ABCG2, because the export of doxorubicin was inhibited by Ko143. The susceptibility of ABCG2 distributed in mitochondria to proteinase K, endoglycosidase H and peptide-N-glycosidase F suggested that ABCG2 in mitochondrial fraction is modified by N-glycans and trafficked through the endoplasmic reticulum and Golgi apparatus and finally localizes within the mitochondria. Thus, it was found that ABCG2 distributed in mitochondria is a functional transporter and that the mitochondrial ABCG2 regulates ALA-mediated PpIX level through PpIX export from mitochondria to the cytosol.
Published Date
2012-11-26
Publication Title
PLoS ONE
Volume
volume7
Issue
issue11
Publisher
Public Library of Science
Start Page
e50082
ISSN
1932-6203
Content Type
Journal Article
language
英語
OAI-PMH Set
岡山大学
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PubMed ID
DOI
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isVersionOf https://doi.org/10.1371/journal.pone.0050082