Colorectal cancer (CRC) is one of the most common and deadly forms of cancer worldwide. While current treatments have improved, many patients still face poor prognosis due to factors like chemoresistance and DNA damage repair mechanisms. Now, a team of researchers has uncovered a promising new approach to tackle CRC by targeting a key molecule involved in DNA damage response – HMGB1.
The study, led by scientists from Binzhou Medical University, reveals that the natural compound glycyrrhizin (GL) can significantly inhibit the progression of CRC by regulating the non-homologous end-joining (NHEJ) DNA repair pathway. Importantly, GL achieves this by targeting HMGB1, a protein that plays a crucial role in DNA damage response and repair.
The researchers found that GL treatment not only reduced cell viability and colony formation in CRC cell lines, but also induced apoptosis and cell cycle arrest. Crucially, GL was able to enhance DNA damage response by increasing the formation of γH2AX foci – a hallmark of DNA double-strand breaks. Further investigation showed that GL’s effects were mediated through the inhibition of the NHEJ pathway, which is typically promoted by HMGB1.
Interestingly, the team also discovered that HMGB1 expression was significantly higher in CRC tissue samples compared to normal adjacent tissues, and was associated with more advanced disease stages and poorer overall survival. This suggests that HMGB1 could be a promising therapeutic target for CRC.
These findings highlight the potential of GL as a natural compound with potent anti-cancer properties, and open up new avenues for the development of more effective CRC treatments targeting the HMGB1-NHEJ axis
Colorectal Cancer: A Persistent Challenge in Cancer Research
Colorectal cancer (CRC) is a major public health concern, ranking as the second leading cause of cancer-related deaths worldwide. Despite advancements in treatment options, many CRC patients still face a grim prognosis, especially those with metastatic or recurrent disease. One of the key challenges in CRC treatment is the ability of cancer cells to evade DNA damage response and repair mechanisms, leading to increased genomic instability and treatment resistance.
Unraveling the Role of HMGB1 in Colorectal Cancer
The high mobility group box 1 (HMGB1) protein has emerged as a critical player in the development and progression of CRC. HMGB1 is a multifunctional protein that plays a crucial role in DNA damage repair, cell signaling, and the tumor microenvironment. Previous studies have shown that HMGB1 can promote the non-homologous end-joining (NHEJ) pathway, the primary mechanism for repairing DNA double-strand breaks in cancer cells.
Glycyrrhizin: A Natural Compound with Untapped Potential
Glycyrrhizin (GL) is a natural compound derived from the licorice plant, Glycyrrhiza glabra. GL has been the subject of increasing attention due to its diverse pharmacological properties, including anti-inflammatory, antioxidant, and anticancer activities. However, the specific mechanisms by which GL influences DNA damage response in CRC remained unclear.
Uncovering the Molecular Mechanisms of GL in Colorectal Cancer
In the recent study, the research team set out to investigate the effects of GL on CRC progression and its underlying mechanisms. They first demonstrated that GL treatment significantly reduced cell viability and colony formation in CRC cell lines, while also inducing apoptosis and cell cycle arrest.
Importantly, the researchers found that GL treatment dramatically increased the formation of γH2AX foci, a hallmark of DNA double-strand breaks, and enhanced DNA damage as evidenced by the comet assay and increased levels of 8-OHdG, a marker of oxidative DNA damage.
Figure 2
Further analysis revealed that GL’s effects on DNA damage response were mediated through the regulation of the NHEJ pathway. The team observed a significant downregulation of key NHEJ-related genes, such as Ku70, Ku80, and XRCC4, upon GL treatment in CRC cells.
Targeting HMGB1: A Promising Approach to Tackle Colorectal Cancer
Intriguingly, the researchers found that GL’s inhibitory effects on CRC progression were dependent on the inhibition of HMGB1. Overexpression of HMGB1 in CRC cells was able to reverse the anti-proliferative and pro-apoptotic effects of GL, as well as the GL-induced upregulation of DNA damage response.
Figure 3
Moreover, the team analyzed HMGB1 expression in CRC tissue samples and found that it was significantly higher in CRC compared to normal adjacent tissues. Importantly, high HMGB1 expression was associated with more advanced disease stages and poorer overall survival in CRC patients.
Implications and Future Directions
The findings of this study have several important implications:
1. Glycyrrhizin as a Promising Anti-Cancer Agent: The study highlights the potential of GL as a natural compound with potent anti-cancer properties, particularly in the context of CRC. GL’s ability to target the HMGB1-NHEJ axis and enhance DNA damage response makes it a promising candidate for further development as a CRC therapeutic.
2. HMGB1 as a Therapeutic Target: The study suggests that HMGB1 could be a valuable biomarker and therapeutic target for CRC. Targeting HMGB1 and its downstream signaling pathways may offer new avenues for more effective CRC treatment.
Figure 4
3. Combination Therapies: Given the complex nature of CRC, the researchers suggest that combining GL with conventional chemotherapeutic agents or other targeted therapies may further enhance the anti-tumor efficacy and overcome treatment resistance.
Moving forward, the research team plans to further investigate the specific mechanisms by which HMGB1 regulates the NHEJ pathway in CRC, as well as explore the potential of GL in combination with other therapeutic approaches. Ultimately, these findings open up new possibilities for the development of more effective and personalized CRC treatments.
Author credit: This article is based on research by Yuhui Han, Wenjiong Sheng, Xiuxin Liu, Haide Liu, Xinyu Jia, Honghui Li, Changyuan Wang, Bin Wang, Tao Hu, Yanchao Ma.
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