title: The therapeutic effects of SET/I2PP2A inhibitors on canine melanoma.
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.
authors.affiliation: Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8515, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Enjoji
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Yabe
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Fujiwara
authors.forename: Shunya
authors.initials: S
authors.lastname: Tsuji
authors.forename: Michael P
authors.initials: MP
authors.lastname: Vitek
authors.forename: Takuya
authors.initials: T
authors.lastname: Mizuno
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Usui
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohama
authors.forename: Koichi
authors.initials: K
authors.lastname: Sato
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D004283:Dog Diseases / Q000188:drug therapy*; D004285:Dogs; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D056488:Histone Chaperones / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008545:Melanoma / Q000188:drug therapy / Q000662:veterinary*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D056488:Histone Chaperones; D009363:Neoplasm Proteins; C583613:OP449 peptide; D010455:Peptides; D014157:Transcription Factors; D000068876:Fingolimod Hydrochloride