2. Academic Validation
  3. An intrinsic purine metabolite AICAR blocks lung tumour growth by targeting oncoprotein mucin 1

An intrinsic purine metabolite AICAR blocks lung tumour growth by targeting oncoprotein mucin 1

  • Br J Cancer. 2023 Feb 21. doi: 10.1038/s41416-023-02196-z.
Fareesa Aftab # 1,  Alice Rodriguez-Fuguet # 1,  Luis Silva # 1,  Ikei S Kobayashi 2,  Jiao Sun 3,  Katerina Politi 4,  Elena Levantini 5 6,  Wei Zhang 3,  Susumu S Kobayashi 2 7,  Wen Cai Zhang 8
Affiliations

Affiliations

  • 1 Department of Cancer Division, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 6900 Lake Nona Boulevard, Orlando, FL, 32827, USA.
  • 2 Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, E/CLS-409, Boston, MA, 02215, USA.
  • 3 Department of Computer Science, College of Engineering and Computer Science, University of Central Florida, 4000 Central Florida Boulevard, Orlando, FL, 32816, USA.
  • 4 Departments of Pathology and Internal Medicine (Section of Medical Oncology) and the Yale Cancer Center, Yale University School of Medicine, New Haven, CT, 06520, USA.
  • 5 Harvard Stem Cell Institute, 330 Brookline Avenue, Harvard Medical School, Boston, MA, 02215, USA.
  • 6 Institute of Biomedical Technologies, National Research Council (CNR), Area della Ricerca di Pisa, 56124, Pisa, Italy.
  • 7 Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, 277-8575, Japan.
  • 8 Department of Cancer Division, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 6900 Lake Nona Boulevard, Orlando, FL, 32827, USA. Wencai.zhang@ucf.edu.
  • # Contributed equally.
PMID: 36810913 DOI: 10.1038/s41416-023-02196-z
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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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