Aberrant upregulation of the endogenous PP2A inhibitor CIP2A is vital for myeloma cell growth and survival

DOI
  • SHIMIZU So
    Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
  • TERAMACHI Jumpei
    Department of Oral Function and Anatomy, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University, Japan
  • HARADA Takeshi
    Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
  • HIASA Masahiro
    Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
  • TENSHIN Hirofumi
    Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
  • ODA Asuka
    Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
  • SEKI Aiko
    Department of Oral Function and Anatomy, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University, Japan
  • INOUE Yusuke
    Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
  • TANIMOTO Kotaro
    Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
  • HIGA Yoshiki
    Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
  • OURA Masahiro
    Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
  • SOGABE Kimiko
    Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
  • HARA Tomoyo
    Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
  • SUMITANI Ryohei
    Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
  • MARUHASHI Tomoko
    Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
  • YAMAGAMI Hiroki
    Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
  • SAWA Yoshihiko
    Department of Oral Function and Anatomy, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University, Japan
  • ENDO Itsuro
    Department of Bioregulatory Sciences, Tokushima University Graduate School of Medical Sciences, Tokushima, Japan
  • TSUNEYAMA Koichi
    Department of Pathology and Laboratory Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
  • MATSUMOTO Toshio
    Fujii Memorial Institute of Medical Sciences, Tokushima University, Tokushima, Japan
  • TANAKA Eiji
    Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
  • ABE Masahiro
    Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan

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<p>The serine/threonine kinase TAK1 is constitutively overexpressed and auto-phosphorylated in multiple myeloma (MM) cells. Protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase which dephosphorylates proteins phosphorylated by various serine/threonine kinases to regulate multiple cellular functions. We recently reported that the serine/threonine kinase TGF-β-activated kinase-1 (TAK1) is highly expressed and auto-phosphorylated to mediate critical growth and survival signaling in MM cells. We demonstrate here that regulation of PP2A activity inversely affects the phosphorylation levels of TAK1 in MM cells, and that MM cells aberrantly overexpress cancerous inhibitor of PP2A (CIP2A), an endogenous inhibitor for PP2A. CIP2A gene silencing as well as treatment with the CIP2A inhibitor TD52 potently induced MM cell death along with suppression of TAK1 expression in MM cells. These results suggest the critical role of PP2A inactivation via CIP2A upregulation in TAK1 phosphorylation and its protein expression and thereby MM cell growth and survival, posing the CIP2A-PP2A axis as an important therapeutic target.</p>

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