Enzyme DDX5 Potentially Enhances Efficacy of Liver Cancer Drug Sorafenib

Researchers at Purdue University have made a groundbreaking discovery regarding the relationship between the enzyme DDX5 and the liver cancer drug sorafenib. The study, published in the journal Cell Death & Disease, suggests that understanding this interaction could lead to improvements in the effectiveness of sorafenib, a drug that currently extends the lives of liver cancer patients by only two to three months. 

Liver cancer is a significant global health concern, with over three-quarters of a million people dying from the disease annually. Survival rates are particularly poor, ranging from less than 10% in some European countries to 30% in Japan, as reported in a 2022 article in the Journal of Hepatology. More than half of liver cancer cases worldwide are attributed to chronic infection by the hepatitis B virus (HBV). 

The lead researcher, Ourania Andrisani, a Distinguished Professor of Basic Medical Sciences at Purdue University, has been studying the role of DDX5 in HBV biosynthesis as part of her broader investigation into the virus. DDX5 is an RNA helicase, a class of proteins that modify the structure of RNA and are involved in various aspects of RNA biology. 

The recent study focused on the relationship between DDX5 and sorafenib, a widely used treatment for liver cancer. While sorafenib is known for its efficacy, its effects are short-lived. By analyzing liver cancer cells and patient records, the researchers found that patients with higher levels of DDX5 tended to live longer than those with lower levels. 

Interestingly, sorafenib itself was found to decrease DDX5 levels in liver cancer cells and animal models. RNA sequencing revealed that the drug activates genes associated with the Wnt/β-catenin pathway, a molecular pathway linked to liver cancer when improperly activated. 

To explore the potential for enhancing sorafenib’s effectiveness, the research team engineered liver cancer cells to boost DDX5 protein levels when treated with the antibiotic doxycycline. When these cells were implanted in mice and treated with sorafenib alongside doxycycline, the tumors were significantly smaller compared to those treated with sorafenib alone. The combination of sorafenib and doxycycline reduced tumor weight by an average of 50% over a two-week period. 

Previous work by Andrisani’s team indicated that DDX5 inhibits HBV replication and helps repress the Wnt/β-catenin pathway. The researchers now propose a potential therapy based on their findings, involving the delivery of mRNA to liver cells to induce the production of DDX5 protein. This approach could specifically target cancer cells within the liver and be administered for the duration of sorafenib treatment, with DDX5 mRNA production ceasing once treatment concludes. 

Andrisani expressed optimism about the potential therapeutic implications of the study, emphasizing the clean and targeted nature of the proposed approach. The hope is that these findings will inspire the development of new therapies that leverage this mechanism to improve outcomes for liver cancer patients. 

In summary, the research at Purdue University sheds light on the intricate relationship between the enzyme DDX5, sorafenib, and liver cancer. The findings open avenues for potential therapeutic interventions that could enhance the anti-tumor efficacy of sorafenib, offering a new perspective on improving outcomes for liver cancer patients. 

Journal Reference  

Zhili Li et al, RNA helicase DDX5 modulates sorafenib sensitivity in hepatocellular carcinoma via the Wnt/β-catenin–ferroptosis axis, Cell Death & Disease (2023). DOI: 10.1038/s41419-023-06302-0