ML792 inhibits growth and TGF-β1-induced EMT of osteosarcoma cells via TGF-β1/Smad and PI3K/AKT pathways

Abstract

Osteosarcoma (OS), a common bone malignancy, is highly metastatic and featured by poor prognosis. SUMOylation is deeply involved in tumorigenesis and cancer progression. SUMO-activating enzyme (SAE) inhibitor has been found to play an anti-proliferative role in multiple cancers. However, their functions in osteosarcoma remain unknown. Based on this, it was hypothesized that ML792, an SAE inhibitor, might be an anti-tumor candidate against osteosarcoma in this paper. The role of ML792 in the treatment of osteosarcoma was investigated in vitro and in vivo. The results showed ML792 significantly arrested human osteosarcoma cells (HOCs) at the G2/M phase, inhibited the proliferation of HOCs, and elicited apoptosis. To better assess the inhibitory role of ML792 in human osteosarcoma, we induced HOCs with TGF-β1. Our study showed that ML792 significantly suppressed the migration, invasion, and EMT of HOCs induced by TGF-β1. Moreover, ML792 inhibited TGF-β1-induced phosphatidylinositol- 3-kinase (PI3K) and AKT activation, as well as Smad2/3 phosphorylation in HOCs. In vivo, ML792 inhibits the growth of osteosarcoma. Thus, ML792 is a promising new antitumor agent to suppress the progress of OS cells undergoing proliferation and EMT by targeting the PI3K/Akt and TGF-β1/Smad pathway and may prevent or reduce the growth and metastasis of osteosarcoma.