TRAF2 inhibits senescence in hepatocellular carcinoma cells via regulating the ROMO1/ NAD+/SIRT3/SOD2 axis.

Abstract

The suppression of tumor proliferation via cellular senescence has emerged as a promising approach for anti-tumor therapy. Tumor necrosis factor receptor-associated factor 2 (TRAF2), an adaptor protein involved in the NF-κB signaling pathway and reactive oxygen species (ROS) production, has been implicated in hepatocellular carcinoma (HCC) proliferation. However, little is currently known about whether TRAF2 promotes HCC development by inhibiting cellular senescence. Replicative senescence model and IR-induced mouse model demonstrated that TRAF2 expression was decrease in senescence cells or liver tissues. Depletion of TRAF2 could inhibit proliferation and arrest the cell cycle via activating p53/p21WAF1 and p16INK4a/pRb signaling pathways in HCC cells and eventually lead to cellular senescence. Mechanistically, TRAF2 deficiency increased the expression of mitochondrial protein reactive oxygen species modulator 1 (ROMO1) and subsequently activated the NAD+/SIRT3/SOD2 pathway to promote the production of ROS and cause mitochondrial dysfunction, which eventually contributed to DNA damage response (DDR). Our findings demonstrate that TRAF2 deficiency inhibits the proliferation of HCC by promoting senescence. Therefore, targeting TRAF2 through various approaches holds therapeutic potential for treating HCC.

• Authors: Jiping Yao, Xue Liang, Siduo Xu, Yanning Liu, Liyan Shui, Shuangshuang Li, Huiting Guo, Zhengyun Xiao, Yongchao Zhao, Min Zheng
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 211 Pg. 47-62 (02 01 2024) ISSN: 1873-4596 [Electronic] United States
• PMID: 38043870 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• NAD
• Reactive Oxygen Species
• Sirtuin 3
• TNF Receptor-Associated Factor 2
• TRAF2 protein, mouse

Topics

• Animals
• Mice
• Carcinoma, Hepatocellular (pathology)
• Cellular Senescence (genetics)
• Liver Neoplasms (pathology)
• NAD (metabolism)
• Reactive Oxygen Species (metabolism)
• Sirtuin 3 (genetics, metabolism)
• TNF Receptor-Associated Factor 2 (genetics)