Pirfenidone inhibits TGF‐β1‐induced metabolic reprogramming during epithelial‐mesenchymal transition in non‐small cell lung cancer

作者：Shuling Zhang, Shuling Zhang, Yuanmei Wang, Daiqin Luo, Zhimei Cheng, Qibing Zeng, Guoze Wang, Mengxue Chen, Shuai Zhang, Shuai Zhang, Peng Luo · 发表于：Journal of Cellular and Molecular Medicine · 年份：2023 · DOI：10.1111/jcmm.18059 · 被引用次数：13 · 研究领域：Cancer, Hypoxia, and Metabolism、Lung Cancer Treatments and Mutations、Pancreatic and Hepatic Oncology Research

Metastasis is an important contributor to increased mortality rates in non-small cell lung cancer (NSCLC). The TGF-β signalling pathway plays a crucial role in facilitating tumour metastasis through epithelial-mesenchymal transition (EMT). Glycolysis, a key metabolic process, is strongly correlated with NSCLC metastasis. Pirfenidone (PFD) has been shown to safely and effectively inhibit TGF-β1 in patients with lung diseases. Furthermore, TGF-β1 and glycolysis demonstrate an interdependent relationship within the tumour microenvironment. Our previous study demonstrated that PFD effectively inhibited glycolysis in NSCLC cells, prompting further investigation into its potential antitumour effects in this context. Therefore, the present study aims to investigate the potential antitumour effect of PFD in NSCLC and explore the relationship among TGF-β1, glycolysis and EMT through further experimentation. The antitumour effects of PFD were evaluated using five different NSCLC cell lines and a xenograft tumour model. Notably, PFD demonstrated a significant antitumour effect specifically in highly glycolytic H1299 cells. To elucidate the underlying mechanism, we compared the efficacy of PFD after pretreatment with either TGF-β1 or a TGF-β receptor inhibitor (LY2109761). The energy metabolomics analysis of tumour tissue demonstrated that PFD, a chemosensitizing agent, reduced lactate and ATP production, thereby inhibiting glycolysis and exerting synergistic antineoplastic effects. Addi...