Role of GRP78 inhibiting artesunate-induced ferroptosis in KRAS mutant pancreatic cancer cells

Objective: To investigate the exact role of GRP78 in artesunate-induced Ferroptosis in KRAS mutant pancreatic Cancer cells. Methods: Artesunate-induced KRAS mutant human pancreatic Cancer cells (AsPC-1 and PaTU8988) Ferroptosis was confirmed by fluorescent staining experiments and CCK8. Western blot and short-hairpin RNA-based knockdown assays were conducted to detect GRP78 activity and its role in artesunate-induced Ferroptosis. Results: Artesunate induced AsPC-1 and PaTU8988 cell death in Ferroptosis manner, rather than necrosis or Apoptosis. In addition, artesunate increased the mRNA and protein levels of GRP78 in a concentration-dependent manner in AsPC-1 and PaTU8988 cells. Knockdown GRP78 enhanced artesunate-induced Ferroptosis of pancreatic Cancer cells in vitro and in vivo. Conclusion: Combining artesunate with GRP78 inhibition may be a novel maneuver for effective killing of KRAS mutant pancreatic ductal adenocarcinoma cells.