Efficacy of an anti-cancer strategy targeting SET in canineosteosarcoma

摘要

Osteosarcoma (OSA) is the most common bone tumor in dogs. Protein phosphatase 2A (PP2A),an evolutionary conserved serine/threonine protein phosphatase, is a crucial tumorsuppressor. SET is a PP2A inhibitory protein that directly interacts with PP2A andsuppresses its phosphatase activity. SET has been reported as a contributor of wide rangeof human and dog tumor malignancies. However, the role of SET in canine OSA (cOSA) remainsunknown. In this study, we investigated the role of SET in cOSA by using 2 cOSA celllines: POS (primary origin) and HM-POS (metastatic origin). Knockdown (KD) of SETexpression was noted to slightly suppress POS cell proliferation only. Furthermore, SET KDeffectively suppressed colony formation ability of both POS and HM-POS cells. SET KD wasobserved to repress ERK1/2, mTOR, E2F1, and NF-κB signaling in HM-POS cells, whereas itinhibited only ERK1/2 signaling in POS. Further, it was observed that SET-targeting drug,FTY720, exerted anti-cancer effects in both POS and HM-POS cells. Moreover, the drug alsoenhanced the anti-cancer effect of cisplatin. The data suggested that a combinationtherapy, based on SET targeting drugs and cisplatin, could be a potent strategy forcOSA.