Quantitative proteomics analysis reveals possible anticancer mechanisms of 5'-deoxy-5'-methylthioadenosine in cholangiocarcinoma cells.
Kankamol KerdkumthongSutthipong NanarongSittiruk RoytrakulThanawat PitakpornpreechaPhonprapavee TantimettaPhanthipha RunsaengSumalee ObchoeiPublished in: PloS one (2024)
Cholangiocarcinoma (CCA) is an aggressive cancer originating from bile duct epithelium, particularly prevalent in Asian countries with liver fluke infections. Current chemotherapy for CCA often fails due to drug resistance, necessitating novel anticancer agents. This study investigates the potential of 5'-deoxy-5'-methylthioadenosine (MTA), a naturally occurring nucleoside, against CCA. While MTA has shown promise against various cancers, its effects on CCA remain unexplored. We evaluated MTA's anticancer activity in CCA cell lines and drug-resistant sub-lines, assessing cell viability, migration, invasion, and apoptosis. The potential anticancer mechanisms of MTA were explored through proteomic analysis using LC-MS/MS and bioinformatic analysis. The results show a dose-dependent reduction in CCA cell viability, with enhanced effects on cancer cells compared to normal cells. Moreover, MTA inhibits growth, induces apoptosis, and suppresses cell migration and invasion. Additionally, MTA enhanced the anticancer effects of gemcitabine on drug-resistant CCA cells. Proteomics revealed the down-regulation of multiple proteins by MTA, affecting various molecular functions, biological processes, and cellular components. Network analysis highlighted MTA's role in inhibiting proteins related to mitochondrial function and energy derivation, crucial for cell growth and survival. Additionally, MTA suppressed proteins involved in cell morphology and cytoskeleton organization, important for cancer cell motility and metastasis. Six candidate genes, including ZNF860, KLC1, GRAMD1C, MAMSTR, TANC1, and TTC13, were selected from the top 10 most down-regulated proteins identified in the proteomics results and were subsequently verified through RT-qPCR. Further, KLC1 protein suppression by MTA treatment was confirmed through Western blotting. Additionally, based on TCGA data, KLC1 mRNA was found to be upregulated in the tissue of CCA patients compared to that of normal adjacent tissues. In summary, MTA shows promising anticancer potential against CCA by inhibiting growth, inducing apoptosis, and suppressing migration and invasion, while enhancing gemcitabine's effects. Proteomic analysis elucidates possible molecular mechanisms underlying MTA's anticancer activity, laying the groundwork for future research and development of MTA as a treatment for advanced CCA.
Keyphrases
- drug resistant
- cell cycle arrest
- induced apoptosis
- multidrug resistant
- signaling pathway
- cell death
- oxidative stress
- mass spectrometry
- acinetobacter baumannii
- endoplasmic reticulum stress
- network analysis
- chronic kidney disease
- gene expression
- end stage renal disease
- escherichia coli
- squamous cell carcinoma
- stem cells
- newly diagnosed
- high resolution
- transcription factor
- locally advanced
- machine learning
- ejection fraction
- big data
- staphylococcus aureus
- label free
- bone marrow
- pseudomonas aeruginosa
- cell migration
- artificial intelligence
- combination therapy
- cystic fibrosis
- radiation therapy
- electronic health record
- climate change
- peritoneal dialysis
- biofilm formation
- patient reported outcomes
- candida albicans
- mesenchymal stem cells
- squamous cell