Pirfenidone inhibits TGF-β1-induced metabolic reprogramming during epithelial-mesenchymal transition in non-small cell lung cancer.
Shuling ZhangYuanmei WangDaiqin LuoZhimei ChengQibing ZengGuoze WangMengxue ChenShuai ZhangPeng LuoPublished in: Journal of cellular and molecular medicine (2023)
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. Additionally, PFD combined with cisplatin targeted TGF-β1 to inhibit glycolysis during EMT and enhanced the chemosensitization of A549 and H1299 cells. The magnitude of the anticancer effect exhibited by PFD was intricately linked to its metabolic properties.
Keyphrases
- transforming growth factor
- epithelial mesenchymal transition
- small cell lung cancer
- induced apoptosis
- signaling pathway
- advanced non small cell lung cancer
- cell cycle arrest
- idiopathic pulmonary fibrosis
- stem cells
- endoplasmic reticulum stress
- mass spectrometry
- risk factors
- cardiovascular disease
- type diabetes
- oxidative stress
- cancer therapy
- cell death
- cardiovascular events