Lung cancer is the leading cause of cancer death and the second most common cancer in the United States. Targeted therapies have led to an increase in survival gains; however, their use is dependent on presence of druggable mutations and hindered by emergence of drug resistance. 5-Aminoimidazole-4-carboxamide 1-ß-d-ribofuranoside (AICAR or Acadesine) is a natural metabolite of de novo purine synthesis pathway, catalyzed by adenylosuccinate lyase (ADSL), and it is a precursor to 5-amino-4-imidazole carboxamide ribonucleoside 5'-phosphate (ZMP). ZMP mimics adenosine monophosphate (AMP) and activates adenosine monophosphate-activated protein kinase (AMPK) and has been shown to specifically induce apoptosis in aneuploid cells. Cell viability assay was used to establish that AICAR can induce cytotoxicity in EGFR and KRAS mutated lung cancer cells irrespective of the mutational status.; thereby, making AICAR a potential anti-cancer drug candidate. However, AICAR's mechanism of cytotoxicity is not understood in lung cancer. FINDSITEcomb2.0 analysis, western blot and thermal shift binding assay identified the cytoplasmic tail of mucin 1 (MUC1-CT), a membrane glycoprotein overexpressed and aberrantly glycosylated in adenocarcinomas, is directly bound and degraded by AICAR. We also found that AICAR can disrupt Janus kinase 1 (JAK1) and MUC1-CT interaction and downregulate JAK1 and epidermal growth factor receptor (EGFR) signaling pathways. Moreover, EGFR mutant patient-derived xenograft tumor and mouse lung tumor tissue-derived organoids showed an enhanced reduction in size with co-treatment of AICAR, EGFR and JAK inhibitors. Moreover, AICAR significantly reduced xenograft tumor weight and size in nude mice without body weight loss Furthermore, MUC1 overexpression rescued AICAR-induced cytotoxicity in H1975 organoids. Therefore, this study is the first to discover MUC1 as the novel binding partner of AICAR and modulator of AICAR's toxicity and the first to show that AICAR can disrupt JAK1-MUC1-CT interaction.
| Identifer | oai:union.ndltd.org:ucf.edu/oai:stars.library.ucf.edu:etd2020-2167 |
| Date | 01 January 2022 |
| Creators | Aftab, Fareesa |
| Publisher | STARS |
| Source Sets | University of Central Florida |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Electronic Theses and Dissertations, 2020- |
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