Understanding the Role of Wnt-Beta Catenin Signaling Pathway in Cancer Progression
Nikhil Prasad Fact checked by:Thailand Medical News Team Mar 18, 2025 5 hours, 35 minutes ago
Medical News: Cancer continues to be one of the leading causes of death worldwide, with researchers constantly seeking new ways to understand its mechanisms and develop more effective treatments. One crucial aspect of cancer development is genomic instability, which occurs when DNA damage is not properly repaired. The Wnt/β-catenin signaling pathway has been widely studied for its role in tumor growth and progression, but new research highlights its impact on DNA damage repair mechanisms as well. Scientists from the Instituto de Medicina y Biología Experimental de Cuyo at the Universidad Nacional de Cuyo in Argentina have explored how this pathway interacts with cellular repair processes, potentially influencing cancer treatment strategies.
Understanding the Role of Wnt-Beta Catenin Signaling Pathway in Cancer Progression
β-Catenin and DNA repair pathways. (a) DNA damage response (DDR). (a) DDR involves a signaling cascade from DNA damage sites, which ultimately activates the cell-cycle checkpoints to allow for repair or triggers cell death. ATM detects DNA double-strand breaks (DSBs), and ATR DNA single-strand breaks (SSBs). MRN complex is another important sensor of DNA damage. γH2AX amplifies the DDR signaling. The downstream effectors CHK1 and CHK2 phosphorylate p53, and p53 are important to activate the DNA repair or to initiate apoptosis. The specific participation of β-catenin and GSK3β in DDR is indicated in the figure. (b) Direct repair. This mechanism specializes in correcting the DNA damage induced by alkylating agents. The most frequent lesion is O6-methylguanine (O6-meG), recognized by O6-meG-DNA-methyltransferase (MGMT) and regulated by β-catenin. (c) Base excision repair (BER). BER is the most versatile DNA repair system for maintaining genome stability. The first step consists of the recognition step by specific DNA glycosylases. Two BER pathways are known: short patch-BER and long patch-BER. The DNA glycosylase excises the DNA damage, leaving an AP site (apurinic/apyrimidinic). AP endonuclease incises the AP site creating a nick, the DNA polymerase β replaces the damaged base in the short patch-BER. However, if the lesion consists of 2–11 nucleotides, PCNA and FEN1 endonuclease, which adds to the process known as long patch-BER. The specific participation of β-catenin in DDR is indicated in the figure, particularly with glycosylases. (d) Nucleotide excision repair (NER). NER is a multi-step system that recognizes a wide spectrum of lesions causing important distortions in DNA and involves the action of more than 30 different proteins. The global genome NER (GG-NER) identifies lesions throughout the genome. XPC-HR23B detects the lesion and additional factors such as TFIIH, XPB, and XPD are essential to unwinding the double helix. XPA-RPA, XPG, and XPF-ERCC1 nucleases are needed to initiate the incision 15-24 nucleotides away. Finally, the gap filling is completed by Polδ/ε, RFC, PCNA, LIG1, LIG3/XRCC1.
DNA damage occurs constantly due to environmental factors and internal cellular processes. Fortunately, the body has multiple repair mechanisms to fix damaged DNA and prevent harmful mutations. However, in cancer cells, these repair systems are often disrupted, leading to uncontrolled cel
l growth. This
Medical News report examines the findings of a recent study that focuses on how the Wnt/β-catenin pathway is connected to DNA damage response (DDR) and repair mechanisms, shedding light on new potential therapeutic approaches.
The Wnt Beta Catenin Pathway and DNA Repair Mechanisms
The Wnt/β-catenin pathway is a signaling network involved in essential cellular processes, including development, tissue maintenance, and cancer progression. It regulates cell differentiation, migration, and survival. In cancer, the pathway is frequently overactivated, contributing to tumor growth, resistance to therapy, and even influencing DNA repair mechanisms.
The study found that Wnt/β-catenin plays a role in several major DNA repair pathways, including:
-Base Excision Repair (BER) - This pathway corrects small DNA damage, such as single base modifications. The researchers found that β-catenin interacts with key proteins involved in BER, influencing the repair of damaged DNA.
-Nucleotide Excision Repair (NER) - This mechanism removes bulky DNA lesions caused by UV radiation and certain chemicals. The study suggests that Wnt signaling may enhance or suppress NER activity depending on the cellular context.
-Mismatch Repair (MMR) - Responsible for fixing errors during DNA replication, MMR is crucial in preventing mutations. The study highlights a link between Wnt/β-catenin activation and impaired MMR function, which could contribute to cancer progression.
-Double-Strand Break Repair (DSBR) - This repair system includes homologous recombination (HR) and non-homologous end joining (NHEJ), two critical pathways for fixing severe DNA breaks. The research found that Wnt signaling influences HR by modulating key repair proteins like BRCA1 and RAD51, impacting cancer cell survival and therapy resistance.
Implications for Cancer Treatment
Understanding the connection between Wnt/β-catenin and DNA repair mechanisms opens new possibilities for targeted cancer therapies. The study suggests that inhibiting the Wnt pathway could enhance the effectiveness of treatments like radiation and chemotherapy by making cancer cells more vulnerable to DNA damage. Some key therapeutic insights include:
-Wnt inhibitors and DNA repair blockers - Combining Wnt pathway inhibitors with drugs that target DNA repair mechanisms could enhance cancer cell sensitivity to treatment.
-Precision medicine approaches - Patients with tumors exhibiting high Wnt activity might benefit from personalized treatments that consider their unique DNA repair deficiencies.
-Overcoming drug resistance - The study highlights how Wnt signaling contributes to therapy resistance, suggesting that targeting this pathway could improve outcomes in resistant cancers.
Conclusion
The Wnt/β-catenin pathway is not only a driver of cancer but also a key player in DNA repair processes. This research provides a deeper understanding of how Wnt signaling interacts with different DNA repair mechanisms, offering valuable insights for the development of new cancer therapies. By targeting the Wnt pathway, scientists hope to create more effective treatments that reduce resistance and improve patient outcomes. Future research should continue exploring the balance between Wnt activity and DNA repair to refine these therapeutic strategies further.
The study findings were published in the peer-reviewed journal: Biology.
https://www.mdpi.com/2079-7737/14/2/185
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