The Disassociation of the A20/HSP90 Complex via Downregulation of HSP90 Restores the Effect of A20 Enhancing the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeted Agents

Frontiers in Oncology

卷:11

Wen-ming Li¹  Jian Zhang²  Shao-jie Xin³  Li-jun Shen⁴  Qi-yu Jiang⁶  Hui-wei Sun⁶  Yan-yao Chai⁶ 

[1] Department of Emergency Medicine, Handan Central Hospital, Handan, Hebei Province, China;

[2] Department of Patient Management, The Fifth Medical Center of Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China;

[3] Division 6, Department of Hepatology, Senior Department of Hepatology, The Fifth Medical Center of Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China;

[4] Division 8, Department of Hepatology, Senior Department of Hepatology, The Fifth Medical Center of Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China;

[5] Medical School of Chinese People’s Liberation Army (PLA), Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China;

[6] Senior Department of Infectious Disease, Institute of Infectious Disease, The Fifth Medical Center of Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China;

关键词: A20;    heat-shock protein 90;    advanced hepatocellular carcinoma;    molecular targeted agents;    drug resistance;   

DOI  :  10.3389/fonc.2021.804412

来源: DOAJ

【 摘 要 】

NF-κB (nuclear factor κB) is a regulator of hepatocellular cancer (HCC)-related inflammation and enhances HCC cells’ resistance to antitumor therapies by promoting cell survival and anti-apoptosis processes. In the present work, we demonstrate that A20, a dominant-negative regulator of NF-κB, forms a complex with HSP90 (heat-shock protein 90) and causes the disassociation of the A20/HSP90 complex via downregulation of HSP90. This process restores the antitumor activation of A20. In clinical specimens, the expression level of A20 did not relate with the outcome in patients receiving sorafenib; however, high levels of HSP90 were associated with poor outcomes in these patients. A20 interacted with and formed complexes with HSP90. Knockdown of HSP90 and treatment with an HSP90 inhibitor disassociated the A20/HSP90 complex. Overexpression of A20 alone did not affect HCC cells. Downregulation of HSP90 combined with A20 overexpression restored the effect of A20. Overexpression of A20 repressed the expression of pro-survival and anti-apoptosis-related factors and enhanced HCC cells’ sensitivity to sorafenib. These results suggest that interactions with HSP90 could be potential mechanisms of A20 inactivation and disassociation of the A20/HSP90 complex and could serve as a novel strategy for HCC treatment.

【 授权许可】

Unknown