Identification of a new TRAF6 inhibitor for the treatment of hepatocellular carcinoma

Int J Biol Macromol. 2021 Jul 1:182:910-920. doi: 10.1016/j.ijbiomac.2021.04.081. Epub 2021 Apr 15.

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.

Keywords: AKT signaling pathway; Bis(4-hydroxy-3,5-dimethylphenyl) sulfone; ERK1/2/p38/MAPK signaling pathway; Hepatocellular carcinoma; TRAF6.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / metabolism
  • Cell Proliferation / drug effects
  • Female
  • Hep G2 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / metabolism
  • MAP Kinase Signaling System
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Sulfones / chemistry
  • Sulfones / pharmacology
  • Sulfones / therapeutic use*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Antineoplastic Agents
  • Intracellular Signaling Peptides and Proteins
  • Sulfones
  • Tifab protein, human
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases