The therapeutic effects of SET/I2PP2A inhibitors on canine melanoma

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  • ENJOJI Shuhei
    Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677–1 Yoshida, Yamaguchi 753–8515, Japan
  • YABE Ryotaro
    Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677–1 Yoshida, Yamaguchi 753–8515, Japan
  • FUJIWARA Nobuyuki
    Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677–1 Yoshida, Yamaguchi 753–8515, Japan
  • TSUJI Shunya
    Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677–1 Yoshida, Yamaguchi 753–8515, Japan
  • VITEK Michael P.
    Department of Neurology, Duke University Medical Center, Durham, NC, U.S.A Oncotide Pharmaceuticals, Inc., Research Triangle Park, NC, U.S.A
  • MIZUNO Takuya
    Laboratory of Molecular Diagnostics and Therapeutics, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677–1 Yoshida, Yamaguchi 753–8515, Japan
  • NAKAGAWA Takayuki
    The Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1–1–1 Yayoi, Bunkyo-ku, Tokyo 113–8657, Japan
  • USUI Tatsuya
    Laboratory of Veterinary Toxicology, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677–1 Yoshida, Yamaguchi 753–8515, Japan
  • OHAMA Takashi
    Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677–1 Yoshida, Yamaguchi 753–8515, Japan
  • SATO Koichi
    Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677–1 Yoshida, Yamaguchi 753–8515, Japan

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Abstract

Canine melanoma is one of the most important diseases in small animal medicine. Protein phosphatase 2A (PP2A), a well conserved serine/threonine phosphatase, plays a critical role as a tumor suppressor. SET/I2PP2A is an endogenous inhibitor for PP2A, which directly binds to PP2A and suppresses its phosphatase activity. Elevated SET protein levels have been reported to exacerbate human tumor progression. The role of SET in canine melanoma, however, has not been understood. Here, we investigated the potential therapeutic role for SET inhibitors in canine melanoma. The expression of SET protein was observed in 6 canine melanoma cell lines. We used CMeC-1 cells (primary origin) and CMeC-2 cells (metastatic origin) to generate cell lines stably expressing SET-targeting shRNAs. Knockdown of SET expression in CMeC-2, but not in CMeC-1, leads to decreased cell proliferation, invasion and colony formation. Phosphorylation level of p70 S6 kinase was decreased by SET knockdown in CMeC-2, suggesting the involvement of mTOR (mammalian target of rapamycin)/p70 S6 kinase signaling. The SET inhibitors, OP449 and FTY720, more effectively killed CMeC-2 than CMeC-1. We observed PP2A activation in CMeC-2 treated with OP449 and FTY720. These results demonstrated the potential therapeutic application of SET inhibitors for canine melanoma.

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