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.
Keywords: ferroptosis, GRP78, artesunate, pancreatic cancer