Identification of a new TRAF6 inhibitor for the treatment of hepatocellular carcinoma
Na Li, Lianxiang Luo, Jiaen Wei, Yong Liu, Neshatul Haque, Hongbin Huang, Yi Qi, Zunnan Huang
Abstract
Tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) is an E3 ubiquitin ligase that plays a crucial role in signal transduction. Previous studies have demonstrated that TRAF6 is overexpressed in hepatocellular carcinoma (HCC) and that TRAF6 knockdown dramatically attenuates tumor cell growth. Thus, TRAF6 may represent a potential therapeutic target for the treatment of HCC. Herein, we identified bis (4-hydroxy-3,5-dimethylphenyl) sulfone (TMBPS) as a novel inhibitor that can directly bind to and downregulate the level of TRAF6. In vitro experimental results showed that TMBPS arrests the cell cycle in the G2/M phase by inactivating the protein kinase B (AKT) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathways and induces apoptosis by activating the p38/mitogen-activated protein kinase (MAPK) signaling pathway. In addition, TMBPS exhibited significant tumor growth inhibition in mouse xenograft models. In summary, our findings offer a proof-of-concept for the use of TMBPS as a novel chemotherapy drug for the prevention or treatment of HCC.