title: Annexin A4 induces platinum resistance in a chloride-and calcium-dependent manner.
abstract: Platinum resistance has long been a major issue in the treatment of various cancers. We previously reported that enhanced annexin A4 (ANXA4) expression, a Ca2+-regulated phospholipid-binding protein, induces chemoresistance to platinum-based drugs. In this study, we investigated the role of annexin repeats, a conserved structure of all the annexin family, responsible for platinum-resistance as well as the effect of knockdown of ANXA4. ANXA4 knockdown increased sensitivity to platinum-based drugs both in vitro and in vivo. To identify the domain responsible for chemoresistance, ANXA4 deletion mutants were constructed by deleting annexin repeats one by one from the C terminus. Platinum resistance was induced both in vitro and in vivo in cells expressing either full-length ANXA4 or the deletion mutants, containing at least one intact annexin repeat. However, cells expressing the mutant without any calcium-binding sites in the annexin repeated sequence, which is essential for ANXA4 translocation from the cytosol to plasma membrane, failed to acquire platinum resistance. After cisplatin treatment, the intracellular chloride ion concentration, whose channel is partly regulated by ANXA4, significantly increased in the platinum-resistant cells. These findings indicate that the calcium-binding site in the annexin repeat induces chemoresistance to the platinum-based drug by elevating the intracellular chloride concentration.
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Japan. Laboratory for Immune Signals, National Institute of Biomedical Innovation, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Morimoto
authors.affiliation: Laboratory for Immune Signals, National Institute of Biomedical Innovation, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Serada
authors.affiliation: Department of Obstetrics and Gynecology, Niigata University Medical School, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Enomoto
authors.affiliation: Laboratory for Immune Signals, National Institute of Biomedical Innovation, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Kim
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Matsuzaki
authors.affiliation: Laboratory for Immune Signals, National Institute of Biomedical Innovation, Japan. Department of Surgery, Osaka University Graduate School of Medicine, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Ueda
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yoshino
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Fujita
authors.affiliation: Laboratory for Immune Signals, National Institute of Biomedical Innovation, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Fujimoto
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Laboratory for Immune Signals, National Institute of Biomedical Innovation, Japan.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Naka
mesh_terms: D000818:Animals; D017314:Annexin A4 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000378:metabolism*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D017314:Annexin A4; D000970:Antineoplastic Agents; D002945:Cisplatin; D002118:Calcium