Photodynamic therapy induces human esophageal carcinoma cell pyroptosis by targeting the PKM2/caspase-8/caspase-3/GSDME axis

• Published in: Cancer letters 2021-11, Vol.520, p.143-159
• Main Authors: Li, Lisha, Song, Dongfeng, Qi, Ling, Jiang, Mingxia, Wu, Yiming, Gan, Junqing, Cao, Kui, Li, Yanjing, Bai, Yuxian, Zheng, Tongsen
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biotechnology; Cancer therapies; Cancer therapy; Carrier Proteins - genetics; Caspase 3 - genetics; Caspase 8 - genetics; Caspase-3; Caspase-8; Cell death; Cell Line, Tumor; Cell Proliferation - drug effects; Chemotherapy; Cisplatin - pharmacology; Esophageal cancer; Esophageal carcinoma; Esophageal Squamous Cell Carcinoma - drug therapy; Esophageal Squamous Cell Carcinoma - genetics; Esophageal Squamous Cell Carcinoma - pathology; Esophagus; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Glycolysis; Heterografts; Humans; Inflammation; Kinases; Male; Membrane Proteins - genetics; Mice; Morphology; Photochemotherapy - methods; Photodynamic therapy; Photosensitizer; Program cell death; Pyroptosis; Pyroptosis - drug effects; Pyroptosis - genetics; Pyruvate kinase; Pyruvic acid; Reagents; Receptors, Estrogen - genetics; Squamous cell carcinoma; Thyroid Hormone-Binding Proteins; Thyroid Hormones - genetics; Tumor necrosis factor-TNF; Warburg effect
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2021.07.014

Photodynamic therapy (PDT) uses a photosensitizer (PS) and visible light to induce cancer cell death. Pyroptosis is a new type of programmed cell death that is associated with the gasdermin protein family. However, the precise mechanism of pyroptosis in PDT-induced suppression of esophageal cancer remains unknown. We demonstrate that PDT can induce gasdermin E (GSDME)-mediated pyroptosis, which is characterized by the formation of pyroptotic blebs in esophageal squamous cell carcinoma (ESCC), which burst and release intracellular contents and pro-inflammatory mediators. Mechanistically, PDT may inhibit pyruvate kinase M2 (PKM2) and consequently, activate caspase-8 and caspase-3, which ultimately releases N-GSDME and triggers pyroptosis in ESCC. Moreover, PDT decreased the efficiency of pyroptosis in the presence of a glycolytic inhibitor. Overall, our results show that PDT induces pyroptosis in ESCC by targeting the PKM2/caspase-8/caspase-3/GSDME axis. This is the first in-depth study of the specific mechanism underlying PKM2-mediated pyroptosis under PDT in ESCC, and potentially has great implications for the clinical application of PDT in ESCC. •PDT can induce pyroptosis in human esophageal carcinoma cells.•PDT can induce pyroptosis by targeting PKM2/caspase-8/caspase-3/GSDME pathway.•2-Deoxy-d-glucose has potential for PDT-induced pyroptosis treatment.