TY - JOUR
T1 - Exploiting the ferroaddiction of pancreatic cancer cells using Fe-doped nanoparticles
AU - Lomphithak, Thanpisit
AU - Sae-Fung, Apiwit
AU - Sprio, Simone
AU - Tampieri, Anna
AU - Jitkaew, Siriporn
AU - Fadeel, Bengt
N1 - Funding Information:
This work was supported by a grant from the Swedish Cancer Foundation awarded to B.F. Additionally, T.L. acknowledges the graduate student scholarships from the Second Century Fund (C2F) and 90th Anniversary Chulalongkorn University Fund. We thank Dr. Florian Salomons, Biomedicum Imaging Core, for advice on live cell imaging.
Publisher Copyright:
© 2023
PY - 2024/1
Y1 - 2024/1
N2 - Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with poor survival rates. Here, we evaluated iron-doped hydroxyapatite (FeHA) as a potential nanomedicine-based approach to combat PDAC. FeHA, in combination with a sublethal dose of the glutathione peroxidase 4 (GPX4) inhibitor RSL3, was found to trigger ferroptosis in KRAS mutant PANC-1 cells, but not in BxPC3 cells, while sparing normal human cells (fibroblasts and peripheral blood mononuclear cells). These findings were recapitulated in 3D spheroids generated using PDAC cells harboring wild-type versus mutant KRAS. Moreover, ferroptosis induction by FeHA plus RSL3 was reversed by the knockdown of STEAP3, a metalloreductase responsible for converting Fe3+ to Fe2+. Taken together, our data show that FeHA is capable of triggering cancer cell death in a KRAS-selective, STEAP3-dependent manner in PDAC cells.
AB - Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with poor survival rates. Here, we evaluated iron-doped hydroxyapatite (FeHA) as a potential nanomedicine-based approach to combat PDAC. FeHA, in combination with a sublethal dose of the glutathione peroxidase 4 (GPX4) inhibitor RSL3, was found to trigger ferroptosis in KRAS mutant PANC-1 cells, but not in BxPC3 cells, while sparing normal human cells (fibroblasts and peripheral blood mononuclear cells). These findings were recapitulated in 3D spheroids generated using PDAC cells harboring wild-type versus mutant KRAS. Moreover, ferroptosis induction by FeHA plus RSL3 was reversed by the knockdown of STEAP3, a metalloreductase responsible for converting Fe3+ to Fe2+. Taken together, our data show that FeHA is capable of triggering cancer cell death in a KRAS-selective, STEAP3-dependent manner in PDAC cells.
KW - Ferroptosis
KW - KRAS
KW - Nanomedicine
KW - Pancreatic adenocarcinoma
KW - STEAP3
UR - http://www.scopus.com/inward/record.url?scp=85176109268&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85176109268&partnerID=8YFLogxK
U2 - 10.1016/j.nano.2023.102714
DO - 10.1016/j.nano.2023.102714
M3 - Article
AN - SCOPUS:85176109268
SN - 1549-9634
VL - 55
JO - Nanomedicine: Nanotechnology, Biology, and Medicine
JF - Nanomedicine: Nanotechnology, Biology, and Medicine
M1 - 102714
ER -