The Role of DDX11 in Enhancing Sensitivity to PARP Inhibitors in Hepatocellular Carcinoma by Modulating BRCA2-RAD51 Mediated Homologous Recombination
Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is associated with high mortality rates worldwide. Despite advances in treatment options, the prognosis for HCC patients remains poor. Therefore, there is an urgent need to identify novel therapeutic targets and strategies to improve patient outcomes.
Poly(ADP-ribose) polymerase (PARP) inhibitors have emerged as a promising class of drugs for the treatment of various cancers, including HCC. PARP inhibitors work by targeting the DNA repair pathway, specifically the base excision repair (BER) pathway. BER is responsible for repairing single-strand DNA breaks, and PARP inhibitors inhibit the repair process, leading to the accumulation of DNA damage and ultimately cell death.
However, not all HCC patients respond equally to PARP inhibitors, highlighting the need to understand the underlying mechanisms that modulate sensitivity to these drugs. Recent studies have identified DDX11, a DNA helicase, as a potential modulator of sensitivity to PARP inhibitors in HCC.
DDX11 plays a crucial role in DNA replication and repair processes. It is involved in the resolution of DNA structures during replication fork restart and is essential for maintaining genomic stability. In HCC, DDX11 has been found to be upregulated and associated with poor prognosis. Interestingly, DDX11 has also been shown to interact with BRCA2 and RAD51, two key proteins involved in homologous recombination (HR), another DNA repair pathway.
HR is a highly accurate DNA repair mechanism that repairs double-strand DNA breaks by using an undamaged sister chromatid as a template. BRCA2 acts as a mediator protein that facilitates the loading of RAD51 onto single-stranded DNA at the site of the break, forming a nucleoprotein filament that promotes strand invasion and subsequent repair.
Recent studies have demonstrated that DDX11 interacts with BRCA2 and RAD51, and its overexpression enhances HR activity. This suggests that DDX11 may play a role in modulating sensitivity to PARP inhibitors by affecting the HR pathway. In HCC cells with high DDX11 expression, the HR pathway may be more active, leading to efficient repair of DNA damage induced by PARP inhibitors and reduced sensitivity to these drugs.
Understanding the role of DDX11 in modulating sensitivity to PARP inhibitors in HCC has important clinical implications. It provides a potential biomarker for predicting patient response to PARP inhibitors and could help identify patients who are more likely to benefit from this treatment strategy. Additionally, targeting DDX11 or its interaction with BRCA2-RAD51 could be a novel therapeutic approach to enhance the sensitivity of HCC cells to PARP inhibitors.
In conclusion, DDX11 plays a critical role in enhancing sensitivity to PARP inhibitors in HCC by modulating the BRCA2-RAD51 mediated HR pathway. Further research is needed to fully elucidate the underlying mechanisms and validate DDX11 as a predictive biomarker and therapeutic target in HCC. Nonetheless, these findings provide valuable insights into the development of personalized treatment strategies for HCC patients and offer hope for improved outcomes in this challenging disease.
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- Source: Plato Data Intelligence.
- Source Link: https://platohealth.ai/targeting-ddx11-promotes-parp-inhibitor-sensitivity-in-hepatocellular-carcinoma-by-attenuating-brca2-rad51-mediated-homologous-recombination-oncogene/