Study summary · research use only
An intrinsic purine metabolite AICAR blocks lung tumour growth by targeting oncoprotein mucin 1
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
Using EGFR-mutant and wild-type human lung cancer cells, plus EGFR-TL transgenic mice and patient- and mouse-derived organoids and tumors, this study examined effects of the purine metabolite AICAR on the oncoprotein mucin 1 (MUC1). AICAR reduced EGFR-mutant tumor cell growth by inducing DNA damage and apoptosis; MUC1 was identified as one of the leading AICAR-binding and degrading proteins, and AICAR negatively regulated JAK signaling and the JAK1-MUC1-CT interaction. Activated EGFR upregulated MUC1-CT expression in EGFR-TL-induced lung tumor tissue, and AICAR reduced EGFR-mutant cell line-derived tumor formation in vivo. Co-treating patient and transgenic mouse lung-tissue-derived tumor organoids with AICAR plus JAK1 and EGFR inhibitors reduced organoid growth. The authors describe AICAR as disrupting protein-protein interactions between MUC1-CT and JAK1 and EGFR in EGFR-mutant lung cancer.
Abstract
Lung cancer cells overexpress mucin 1 (MUC1) and active subunit MUC1-CT. Although a peptide blocks MUC1 signalling, metabolites targeting MUC1 are not well studied. AICAR is a purine biosynthesis intermediate. Cell viability and apoptosis were measured in AICAR-treated EGFR-mutant and wild-type lung cells. AICAR-binding proteins were evaluated by in silico and thermal stability assays. Protein-protein interactions were visualised by dual-immunofluorescence staining and proximity ligation assay. AICAR-induced whole transcriptomic profile was determined by RNA sequencing. EGFR-TL transgenic mice-derived lung tissues were analysed for MUC1 expression. Organoids and tumours from patients and transgenic mice were treated with AICAR alone or in combination with JAK and EGFR inhibitors to evaluate treatment effects. AICAR reduced EGFR-mutant tumour cell growth by inducing DNA damage and apoptosis. MUC1 was one of the leading AICAR-binding and degrading proteins. AICAR negatively regulated JAK signalling and JAK1-MUC1-CT interaction. Activated EGFR upregulated MUC1-CT expression in EGFR-TL-induced lung tumour tissues. AICAR reduced EGFR-mutant cell line-derived tumour formation in vivo. Co-treating patient and transgenic mouse lung-tissue-derived tumour organoids with AICAR and JAK1 and EGFR inhibitors reduced their growth. AICAR represses the MUC1 activity in EGFR-mutant lung cancer, disrupting protein-protein interactions between MUC1-CT and JAK1 and EGFR.
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