Anticancer Drug-Induced Epithelial-Mesenchymal Transition via p53/miR-34a axis in A549/ABCA3 Cells

• Main Authors: Ayano Yamamoto (Author), Masashi Kawami (Author), Takashi Konaka (Author), Shinnosuke Takenaka (Author), Ryoko Yumoto (Author), Mikihisa Takano (Author)
• Format: Book
• Published: Frontiers Media S.A., 2019-10-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.18433/jpps30660; 1482-1826
• Keywords: Therapeutics. Pharmacology; RM1-950; Pharmacy and materia medica; RS1-441
• Source: Journal of Pharmacy & Pharmaceutical Sciences, Vol 22, Iss 1 (2019)

PURPOSE. Several anticancer drugs including bleomycin (BLM) and methotrexate (MTX) cause serious lung diseases such as pulmonary fibrosis. Although evidences showing the association of epithelial-mesenchymal transition (EMT) with pulmonary fibrosis are increasing, the mechanism underlying anticancer drug-induced EMT has been poorly understood. On the other hand, miR-34a, a non-coding small RNA, has been highlighted as a key factor to regulate EMT in lung. In this study, we elucidated the role of miR-34a in anticancer drug-induced EMT using A549/ABCA3 cells as a novel type II alveolar epithelium model. METHODS. Expression levels of α-smooth muscle actin (α-SMA) mRNA, miR-34a, and p53 were evaluated by real-time PCR and western blot analysis, respectively. RESULTS. BLM and MTX induced EMT-like morphological changes and increase in mRNA expression level of α-SMA, an EMT marker. Also, both drugs increased the expression level of miR-34a. Furthermore, mRNA expression level of α-SMA was enhanced by introduction of miR-34a mimic into A549/ABCA3 cells. To examine the mechanism underlying drug-induced enhancement of miR-34a expression, we focused on p53/miR-34a axis. Both drugs upregulated protein expression of p53, an inducer of miR-34a, as well as phosphorylation of Ser15 in p53. CONCLUSIONS. These findings indicated that p53/miR-34a axis may contribute to anticancer drug-induced EMT in type II alveolar epithelial cells.