The therapeutic effects of SET/I2PP2A inhibitors on canine melanoma.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Enjoji, S; Yabe, R; Fujiwara, N; Tsuji, S; Vitek, MP; Mizuno, T; Nakagawa, T; Usui, T; Ohama, T; Sato, K

Published Date

  • November 2015

Published In

Volume / Issue

  • 77 / 11

Start / End Page

  • 1451 - 1456

PubMed ID

  • 26062569

Pubmed Central ID

  • 26062569

Electronic International Standard Serial Number (EISSN)

  • 1347-7439

Digital Object Identifier (DOI)

  • 10.1292/jvms.15-0193

Language

  • eng

Conference Location

  • Japan