| 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. |
