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

Abstract

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.

• Authors: Kang Wang, Zhengyang Zhang, Ming Wang, Xiongfeng Cao, Jianchen Qi, Dongqing Wang, Aihua Gong, Haitao Zhu
• Journal: Drug design, development and therapy (Drug Des Devel Ther) Vol. 13 Pg. 2135-2144 ( 2019) ISSN: 1177-8881 [Electronic] New Zealand
• PMID: 31456633 (Publication Type: Journal Article)

Chemical References

• Endoplasmic Reticulum Chaperone BiP
• HSPA5 protein, human
• Heat-Shock Proteins
• Hspa5 protein, mouse
• KRAS protein, human
• RNA, Small Interfering
• Artesunate
• Proto-Oncogene Proteins p21(ras)

Topics

• Animals
• Artesunate (antagonists & inhibitors, pharmacology)
• Endoplasmic Reticulum Chaperone BiP
• Female
• Ferroptosis (drug effects)
• Heat-Shock Proteins (antagonists & inhibitors, metabolism)
• Humans
• Lipid Peroxidation (drug effects)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mutation
• Neoplasms, Experimental (drug therapy, metabolism, pathology)
• Pancreatic Neoplasms (drug therapy, metabolism, pathology)
• Proto-Oncogene Proteins p21(ras) (antagonists & inhibitors, genetics, metabolism)
• RNA, Small Interfering (pharmacology)
• Tumor Cells, Cultured