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1.
Br J Cancer ; 128(9): 1647-1664, 2023 05.
Article in English | MEDLINE | ID: mdl-36810913

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.


Subject(s)
ErbB Receptors , Lung Neoplasms , Mice , Animals , ErbB Receptors/genetics , ErbB Receptors/metabolism , Mucin-1/genetics , Mucin-1/metabolism , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung/metabolism , Mice, Transgenic , Oncogene Proteins , Purines , Cell Line, Tumor
2.
Cancer Res Commun ; 3(6): 1013-1025, 2023 06.
Article in English | MEDLINE | ID: mdl-37377607

ABSTRACT

Recent preclinical studies have linked antidepressants (AD) to their potential anticancer effects in multiple cancers, but the impact on lung cancer remains unclear. This meta-analysis examined the associations between ADs and lung cancer incidence and survival. The Web of Science, Medline, CINAHL, and PsycINFO databases were searched to identify eligible studies published by June 2022. We conducted a meta-analysis using a random-effects model to compare the pooled risk ratio (RR) and 95% confidence interval (CI) in those treated with or without ADs. Heterogeneity was examined using Cochran Q test and inconsistency I2 statistics. The methodologic quality of the selected studies was assessed using the Newcastle-Ottawa Scale for observational studies. Our analysis, including 11 publications involving 1,200,885 participants, showed that AD use increased lung cancer risk by 11% (RR = 1.11; 95% CI = 1.02-1.20; I2 = 65.03%; n = 6) but was not associated with overall survival (RR = 1.04; 95% CI = 0.75-1.45; I2 = 83.40%; n = 4). One study examined cancer-specific survival. Subgroup analysis showed that serotonin and norepinephrine reuptake inhibitors (SNRIs) were associated with an increased lung cancer risk by 38% (RR = 1.38; 95% CI = 1.07-1.78; n = 2). The quality of selected studies was good (n = 5) to fair (n = 6). Our data analysis suggests that SNRIs were associated with an elevated risk of lung cancer, raising concerns regarding the use of AD treatment in patients vulnerable to lung cancer. The effects of ADs-particularly SNRIs-and their interplay with cigarette use and lung cancer risk in vulnerable patients merits further study. Significance: In this meta-analysis of 11 observational studies, we found evidence of a statistically significant association between the use of certain ADs and lung cancer risk. This effect merits further study, particularly as it relates to known environmental and behavioral drivers of lung cancer risk, such as air pollution and cigarette smoke.


Subject(s)
Lung Neoplasms , Serotonin and Noradrenaline Reuptake Inhibitors , Humans , Antidepressive Agents/adverse effects , Selective Serotonin Reuptake Inhibitors/adverse effects , Lung Neoplasms/epidemiology , Observational Studies as Topic
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