title: Annexin A4-conferred platinum resistance is mediated by the copper transporter ATP7A.
abstract: Although platinum drugs are often used for the chemotherapy of human cancers, platinum resistance is a major issue and may preclude their use in some cases. We recently reported that enhanced expression of Annexin A4 (Anx A4) increases chemoresistance to carboplatin through increased extracellular efflux of the drug. However, the precise mechanisms underlying that chemoresistance and the relationship of Anx A4 to platinum resistance in vivo remain unclear. In this report, the in vitro mechanism of platinum resistance induced by Anx A4 was investigated in endometrial carcinoma cells (HEC1 cells) with low expression of Anx A4. Forced expression of Anx A4 in HEC1 cells resulted in chemoresistance to platinum drugs. In addition, HEC1 control cells were compared with Anx A4-overexpressing HEC1 cells in xenografted mice. Significantly greater chemoresistance to cisplatin was observed in vivo in Anx A4-overexpressing xenografted mice. Immunofluorescence analysis revealed that exposure to platinum drugs induced relocation of Anx A4 from the cytoplasm to the cellular membrane, where it became colocalized with ATP7A, a copper transporter also well known as a mechanism of platinum efflux. ATP7A expression suppressed by small interfering RNA had no effect on HEC1 control cells in terms of chemosensitivity to platinum drugs. However, suppression of ATP7A in Anx A4-overexpressing platinum-resistant cells improved chemosensitivity to platinum drugs (but not to 5-fluorouracil) to a level comparable to that of control cells. These results indicate that enhanced expression of Anx A4 confers platinum resistance by promoting efflux of platinum drugs via ATP7A.
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan; Laboratory for Immune Signal, National Institute of Biomedical Innovation, Osaka, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Matsuzaki
authors.forename: Takayuki
authors.initials: T
authors.lastname: Enomoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Serada
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yoshino
authors.forename: Shushi
authors.initials: S
authors.lastname: Nagamori
authors.forename: Akiko
authors.initials: A
authors.lastname: Morimoto
authors.forename: Takuhei
authors.initials: T
authors.lastname: Yokoyama
authors.forename: Ayako
authors.initials: A
authors.lastname: Kim
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kimura
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Ueda
authors.forename: Masami
authors.initials: M
authors.lastname: Fujita
authors.forename: Minoru
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Kanai
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kimura
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Naka
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017314:Annexin A4 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001692:Biological Transport; D016190:Carboplatin / Q000494:pharmacology*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D000073840:Copper-Transporting ATPases; D019008:Drug Resistance, Neoplasm; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D034622:RNA Interference; D034741:RNA, Small Interfering; D023041:Xenograft Model Antitumor Assays
chemical_list: D017314:Annexin A4; D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D034741:RNA, Small Interfering; D016190:Carboplatin; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases; D002945:Cisplatin; D005472:Fluorouracil
keywords: ATP7A; Annexin A4; copper transporter; platinum resistance; platinum transporter