Abstract
As a therapeutic approach, epigenetic modifiers have the potential to enhance the efficacy of chemotherapeutic agents. Protein arginine methyltransferase 5 (PRMT5), highly expressed in lung adenocarcinoma, was identified to be involved in tumorigenesis. In the current study, we examined the potential antineoplastic activity of PRMT5 inhibitor, arginine methyltransferase inhibitor 1 (AMI-1), and cisplatin on lung adenocarcinoma. Bioinformatic analyses identified apoptosis, DNA damage, and cell cycle progression as the main PRMT5-associated functional pathways, and survival analysis linked the increased PRMT5 gene expression to worse overall survival in lung adenocarcinoma. Combined AMI-1 and cisplatin treatment significantly reduced cell viability and induced apoptosis. Cell cycle arrest in A549 and DMS 53 cells was evident after AMI-1, and was reinforced after combination treatment. Western blot analysis showed a reduction in demethylation histone 4, a PRMT5- downstream target, after treatment with AMI-1 alone or in combination with cisplatin. While the combination approach tackled lung cancer cell survival, it exhibited cytoprotective abilities on HBEpC (normal epithelial cells). The survival of normal bronchial epithelial cells was not affected by using AMI-1. This study highlights evidence of novel selective antitumor activity of AMI-1 in combination with cisplatin in lung adenocarcinoma cells.
Highlights
Lung cancer is one of the most prevalent cancers worldwide
We aim to explore the effect of the combination of Protein arginine methyltransferase 5 (PRMT5) inhibitor (AMI-1) and cisplatin on cell viability in an in vitro lung cancer model, compared with normal bronchial epithelial cells
The survival analyses of publicly available lung cancer data revealed that an increased level of PRMT5 gene expression was significantly linked to worse overall survival (OS) in lung adenocarcinoma with the pooled hazard ratio (HR) of 1.31
Summary
Lung cancer is one of the most prevalent cancers worldwide. According to the 2018 report of the WHO International Agency for Research on cancer, lung cancer is the most commonly diagnosed cancer, with 2.09 million cases (11.6% of the total cases) in both sexes, and the leading cause of cancer death (18.4% of the total cancer deaths), [1]. Instances of recurrence and metastasis are high in lung cancer, urging the development of novel therapeutic options. The carcinogenesis of lung cancer is steered by the acquisition of genetic and epigenetic alterations. Epigenetic modifications, such as DNA methylation, histone modifications, and non-coding RNA expression, have been extensively implicated in lung cancer [3]. The frequency of such epigenetic events increases with the progression of the disease. The methylation of promoters of specific genes (e.g., TAC1, HOXA7, and SOX17) in sputum and blood are strongly correlated with the risk of lung cancer. The reversible nature of epigenetic aberrations has made its correction an attractive therapeutic approach
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