Novel Way to Overcome Chemotherapeutic Drug Resistance in Liver Cancer

Chinese Academy of Sciences

Hepatocellular carcinoma (HCC) is the most common form of liver cancer. Targeted drugs are promising for advanced HCC.

Bortezomib (BTZ), a selective proteasome inhibitor, has shown potential against liver cancer. However, like many other chemotherapeutic agents, BTZ drug resistance remains to be a major issue in the treatment of advanced HCC patients.

A research group led by Assoc. Prof. CHEN Liang at the Shenzhen Institute of Advanced Technology (SIAT) of the Chinese Academy of Sciences reported a novel way to overcome drug resistance in HCC chemotherapy.

The study was published in Clinical and Translational Medicine on Jan. 21.

The researchers constructed multiple tumor cell lines and mouse model, and proved that TRIM28 activated the expression of several core subunits of the proteasome and further promoted proteasome assembly and activity. These effects were more pronounced upon the treatment of the proteasome inhibitor Bortezomib.

“Mechanistically, TRIM28 enters the nucleus and binds to the promoter of various proteasome subunits, leading to increased transcriptional activation of these genes,” said CHEN.

They found that TRIM28-proteasome axis was the key to BTZ sensitivity in HCC cells, and the suppression of this axis would bring better treatment of HCC in vitro and in vivo.

In line with these observations, TRIM28 promoted the expression of proteasome subunits as well as BTZ-mediated cell killing in HCC tissues. The TRIM28-mediated modulation of the proteasome activity would allow convenient control of proteasome functioning and could be easily adapted for HCC therapy.

These findings show a novel activator of the proteasome and its roles in BTZ-mediated HCC treatment, and provide a potential synergistic therapeutic strategy for HCC intervention.

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