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Exploiting network-based drug repositioning to target metastasis in colorectal cancer: In-Silico prediction and
Mohammad Javad Bazyari1, Ali Ahmadizad Firouzjaei2, Seyed Mahdi Ahmadi1
1Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Abstract:
Metastasis is a major challenge in colorectal cancer (CRC) treatment. The incidence of regional and distant stages has increased during the past decade and the 5-year survival of metastatic CRC patients is 20 %. Although there is a necessity to develop systematic treatment, the cost and time of novel drug discovery hinder this progress. Drug repositioning simplifies this process by accelerating regulatory processes in drug discovery. Here we used a systems biology approach to find key player genes in the metastasis. First, we found differentially expressed genes in metastatic tissue compared to primary tumors. Then, we constructed and analyzed the protein-protein interaction (PPI) network to find hub genes and subjected them to query in the DrugBank database. We found plasminogen (PLG) is the hub gene in the constructed PPI network and tranexamic acid (TXA) is its known inhibitor with clinically approved antifibrinolytic activity. Pathway enrichment analysis showed that PLG is involved in matrix remodeling, Platelet activation, and cell energy production through insulin-growth factor uptake in colorectal cancer cells which are important processes during metastasis. We further explored the CPTAC-COAD proteomics data and found that the PLG level is significantly higher in stage IV compared to stage I. Interestingly, we found that PLG is correlated with mutation rate. We then investigated the effect of TXA on SW480 cells' mobility and migration by scratch assay and transwell migration assay. Both assays indicated that TXA can significantly inhibit the cells' migratory potential.
Insights
Drug repositioning identified plasminogen (PLG) as a key gene in colorectal cancer (CRC) metastasis. Its inhibitor, tranexamic acid (TXA), significantly reduced cancer cell migration, offering a potential new treatment strategy for metastatic CRC.
Area of Science:
- Oncology
- Systems Biology
- Pharmacology
Background:
- Metastasis is a critical challenge in colorectal cancer (CRC) treatment, with a 5-year survival rate of only 20% for metastatic patients.
- Novel drug discovery for metastatic CRC is hindered by high costs and long timelines.
- Drug repositioning offers a faster, more cost-effective approach to identify new therapeutic strategies.
Purpose of the Study:
- To identify key genes involved in colorectal cancer metastasis using a systems biology approach.
- To explore the potential of drug repositioning for metastatic CRC treatment.
- To investigate plasminogen (PLG) as a potential therapeutic target and its inhibitor, tranexamic acid (TXA), as a treatment option.
Main Methods:
- Differential gene expression analysis between primary and metastatic CRC tissues.
- Construction and analysis of protein-protein interaction (PPI) networks to identify hub genes.
- Querying the DrugBank database for known inhibitors of identified hub genes.
- Pathway enrichment analysis to understand the biological roles of hub genes.
- Proteomic data analysis (CPTAC-COAD) to correlate gene expression with clinical stages.
- In vitro assays (scratch and transwell migration) to evaluate the effect of TXA on CRC cell migration.
Main Results:
- Plasminogen (PLG) was identified as a crucial hub gene in the CRC metastasis PPI network.
- Tranexamic acid (TXA), an established antifibrinolytic drug, was identified as a PLG inhibitor.
- PLG is implicated in matrix remodeling, platelet activation, and energy metabolism crucial for metastasis.
- PLG levels are significantly elevated in stage IV CRC and correlate with mutation rates.
- TXA treatment significantly inhibited the migration and mobility of SW480 colorectal cancer cells.
Conclusions:
- Plasminogen (PLG) plays a significant role in colorectal cancer metastasis.
- Tranexamic acid (TXA) demonstrates potential as a repositioned drug to inhibit CRC cell migration.
- This study highlights a systems biology-driven approach for identifying novel therapeutic targets and drug repositioning opportunities in metastatic CRC.
