Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is a significant challenge to China’s public health system because of the high infection rates with hepatitis virus [1]
Expression levels of A20 were much lower in L-02, a non-tumor hepatic cells line, than in hepatocellular cancer (HCC) cells (Figure 1B)
The survival analysis of the two groups showed that there was no correlation between expression levels of A20 and outcome patients receiving sorafenib (Figures 1D, E and Table 1), and there was no significant difference in the survival time between the two groups (Figures 1D, E and Table 1)
Summary
Hepatocellular carcinoma (HCC) is a significant challenge to China’s public health system because of the high infection rates with hepatitis virus [1]. Targeted molecular drugs represented by sorafenib in several clinical trials were shown to prolong survival and improve quality of life, molecular targeted therapy is associated with many problems: [1] sorafenib treatment produces drug resistance and severe side effects [9]; [2] in addition to sorafenib, new molecular targeted drugs such as lenvatinib, regorafenib, and cabozantinib have been marketed [10,11,12] These drugs are considered superior to sorafenib, they have similar structural features and the same chemical structure as sorafenib (1-(4-(pyridin-4-yloxy)phenyl) urea). It has become essential to research and explore the resistance mechanism of HCC cells to molecularly targeted drugs to develop new and more effective treatment strategies to achieve the same and better anti-tumor effects with smaller doses of drugs
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