The therapeutic effects of SET/I2PP2A inhibitors on caninemelanoma

Journal of Veterinary Medical Science

Ryotaro YABE²  Shuhei ENJOJI²  Takuya MIZUNO¹  Tatsuya USUI⁵  Takayuki NAKAGAWA³  Koichi SATO²  Michael P. VITEK⁴  Takashi OHAMA²  Shunya TSUJI²  Nobuyuki FUJIWARA² 

[1] Laboratory of Molecular Diagnostics and Therapeutics, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677�?1 Yoshida, Yamaguchi 753�?8515, Japan;Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677�?1 Yoshida, Yamaguchi 753�?8515, Japan;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;Department of Neurology, Duke University Medical Center, Durham, NC, U.S.A;Laboratory of Veterinary Toxicology, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677�?1 Yoshida, Yamaguchi 753�?8515, Japan

关键词: canine;    melanoma;    PP2A;    SET;   

DOI  :  10.1292/jvms.15-0193

学科分类：兽医学

来源: Japanese Society of Veterinary Science

【 摘 要 】

References(22)Cited-By(1)Canine melanoma is one of the most important diseases in small animal medicine.Protein phosphatase 2A (PP2A), a well conserved serine/threonine phosphatase, plays acritical role as a tumor suppressor. SET/I2PP2A is an endogenous inhibitor for PP2A, whichdirectly binds to PP2A and suppresses its phosphatase activity. Elevated SET proteinlevels have been reported to exacerbate human tumor progression. The role of SET in caninemelanoma, however, has not been understood. Here, we investigated the potentialtherapeutic role for SET inhibitors in canine melanoma. The expression of SET protein wasobserved in 6 canine melanoma cell lines. We used CMeC-1 cells (primary origin) and CMeC-2cells (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 cellproliferation, invasion and colony formation. Phosphorylation level of p70 S6 kinase wasdecreased by SET knockdown in CMeC-2, suggesting the involvement of mTOR (mammalian targetof rapamycin)/p70 S6 kinase signaling. The SET inhibitors, OP449 and FTY720, moreeffectively killed CMeC-2 than CMeC-1. We observed PP2A activation in CMeC-2 treated withOP449 and FTY720. These results demonstrated the potential therapeutic application of SETinhibitors for canine melanoma.

【 授权许可】

Unknown