title: Functional evidence for Eme1 as a marker of cisplatin resistance.
abstract: The ability to predict cisplatin sensitivity in tumors has been expected to greatly improve the outcome of cancer therapy, because the drug is frequently used in a variety of tumors. Although ERCC1 and other repair proteins have been investigated as markers of cisplatin resistance, reliable markers are still needed. Here, we demonstrate that Eme1 levels can predict cisplatin sensitivity more accurately than ERCC1 or Rad51 levels in a variety of human cancer cell lines. Eme1 forms a heterodimeric protein complex with Mus81 and functions as a structure-specific endonuclease. Haploinsufficiency of Eme1 led to hypersensitivity to cisplatin in the colon cancer cell line HCT116. On the basis of this finding, we examined the relationships between levels of proteins involved in the repair of interstrand cross-links and cisplatin sensitivity in human tumor cell lines with a variety of origins. Although ERCC1, Rad51 and Mus81 levels correlated with sensitivity to some extent, the clearest correlation was observed with Eme1. Tumors with low Eme1 levels were more sensitive to the drug than tumors with high levels. This suggests that the measurement of Eme1 in tumors may be more informative for cisplatin-based chemotherapy than that of the currently available markers.
authors.affiliation: Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Tomoda
authors.forename: Mari
authors.initials: M
authors.lastname: Katsura
authors.forename: Miyuki
authors.initials: M
authors.lastname: Okajima
authors.forename: Noriko
authors.initials: N
authors.lastname: Hosoya
authors.forename: Nobuoki
authors.initials: N
authors.lastname: Kohno
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Miyagawa
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015152:Blotting, Northern; D015153:Blotting, Western; D002945:Cisplatin / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004706:Endodeoxyribonucleases / Q000235:genetics / Q000378:metabolism*; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D051135:Rad51 Recombinase; C071447:ERCC1 protein, human; C507947:Eme1 protein, human; D004706:Endodeoxyribonucleases; D004720:Endonucleases; C498772:MUS81 protein, human; D002945:Cisplatin