Annexin A4 induces platinum resistance in a chloride-and calcium-dependent manner
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Akiko Morimoto1,2, Satoshi Serada2, Takayuki Enomoto3, Ayako Kim2, Shinya Matsuzaki1 ,Tsuyoshi Takahashi2,4 ,Yutaka Ueda1, Kiyoshi Yoshino1, Masami Fujita1, Minoru Fujimoto2, Tadashi Kimura1 and Tetsuji Naka2
1 Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Japan
2 Laboratory for Immune Signals, National Institute of Biomedical Innovation, Japan
3 Department of Obstetrics and Gynecology, Niigata University Medical School, Japan
4 Department of Surgery, Osaka University Graduate School of Medicine, Japan
Tetsuji Naka , email:
Keywords: Annexin A4; platinum resistance; annexin repeat; chloride ion
Received: April 04, 2014 Accepted: August 03, 2014 Published: August 04, 2014
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.
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