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

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.