Journal
DRUG DESIGN DEVELOPMENT AND THERAPY
Volume 13, Issue -, Pages 2135-2144Publisher
DOVE MEDICAL PRESS LTD
DOI: 10.2147/DDDT.S199459
Keywords
ferroptosis; GRP78; artesunate; pancreatic cancer
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Funding
- National Natural Science Foundation of China [81502663]
- Social Development Foundation of Jiangsu Province [BE2018691]
- Young Medical Talents of Jiangsu [QNRC20168339]
- Postgraduate Innovation Project of Jiangsu Province [KYCX17_1802]
- Six talent peals project of Jiangsu Province [WSW-039]
- Six for one project of Jiangsu Province [LGY2018093]
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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.
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