Steroidal saponins PPI/CCRIS/PSV induce cell death in pancreatic cancer cell through GSDME-dependent pyroptosis

• Published in: Biochemical and biophysical research communications Vol. 673; pp. 51 - 58
• Main Authors: Liu, Yang, Zhang, Weitao, Zhou, Haoyan, Chen, Jun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.09.2023
• Subjects: Animals; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Diosgenin - pharmacology; Diosgenin - therapeutic use; Female; Gasdermins - metabolism; Humans; Lactate Dehydrogenases; Mice; Mice, Inbred BALB C; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Phosphate-Binding Proteins - metabolism; Pyroptosis - drug effects; Saponins - pharmacology; Saponins - therapeutic use; Xenograft Model Antitumor Assays
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2023.06.062

Pancreatic cancer is highly aggressive and lethal, and treatment options for it are limited. Gasdermin E (GSDME) is highly expressed in pancreatic cancer and can induce pyroptosis. In this type of programmed cell death, cells swell and emit large gas bubbles through their plasma membranes. Hence, GSDME induction is potentially an efficacious therapeutic approach against pancreatic cancer. In the present study, we found that the steroidal saponins polyphyllin I (PPI), collettiside III (CCRIS), and paris saponin V (PSV) significantly inhibited PANC-1, AsPC-1, and BxPC-3 cell proliferation. PPI/CCRIS/PSV altered the morphology of PANC-1 cells and induced the release of lactate dehydrogenase (LDH) from them. Therefore, these three constituents caused PANC-1 cells to undergo pyroptosis. This conclusion was confirmed by propidium iodide (PI) staining and flow cytometry assays. The present work also revealed that PPI/CCRIS/PSV induced pyroptosis via GSDME rather than gasdermin D (GSDMD). Whereas PPI/CCRIS/PSV induced caspase-3 to cleave GSDME, it had no such effect on GSDMD. We also established a PANC-1 xenograft tumor model in BALB/c nude mice and administered CCRIS to them as this compound demonstrated the most substantial pyroptotic effect in the in vitro experiments. This treatment significantly inhibited tumor growth in the mice by activating GSDME-dependent pyroptosis. This research demonstrates demonstrate that pyroptosis induction by PPI/CCRIS/PSV has important implications in basic science and clinical medicine. Future investigations should endeavor to determine the benefits and risks associated with the administration of these steroidal saponins as anti-PDAC therapy. [Display omitted] •Steroidal saponins PPI/CCRIS/PSV could inhibit the growth of several PDAC cells.•PPI/CCRIS/PSV triggered cell pyroptosis in PDAC cells by activating caspase-3 to cleave GSDME.•CCRIS significantly suppressed the development of PANC-1 xenograft tumor by inducing GSDME-mediated pyroptosis.•Pyroptosis induction based on GSDME in PDAC could be a potential strategy for the treatment of pancreatic cancer.