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FSP1 confers ferroptosis resistance in KEAP1 mutant non-small cell lung carcinoma in NRF2-dependent and -independent manner

Authors
 Jong Woo Kim  ;  Min-Ju Kim  ;  Tae-Hee Han  ;  Ji-Yoon Lee  ;  Sangok Kim  ;  Hyerin Kim  ;  Kyoung-Jin Oh  ;  Won Kon Kim  ;  Baek-Soo Han  ;  Kwang-Hee Bae  ;  Hyun Seung Ban  ;  Soo Han Bae  ;  Sang Chul Lee  ;  Haeseung Lee  ;  Eun-Woo Lee 
Citation
 CELL DEATH & DISEASE, Vol.14(8) : 567, 2023-08 
Journal Title
CELL DEATH & DISEASE
Issue Date
2023-08
MeSH
Carcinoma, Non-Small-Cell Lung* / genetics ; Ferroptosis* / genetics ; Humans ; Kelch-Like ECH-Associated Protein 1 / genetics ; Lung Neoplasms* / genetics ; NF-E2-Related Factor 2 / genetics
Abstract
Ferroptosis, a type of cell death induced by lipid peroxidation, has emerged as a novel anti-cancer strategy. Cancer cells frequently acquire resistance to ferroptosis. However, the underlying mechanisms are poorly understood. To address this issue, we conducted a thorough investigation of the genomic and transcriptomic data derived from hundreds of human cancer cell lines and primary tissue samples, with a particular focus on non-small cell lung carcinoma (NSCLC). It was observed that mutations in Kelch-like ECH-associated protein 1 (KEAP1) and subsequent nuclear factor erythroid 2-related factor 2 (NRF2, also known as NFE2L2) activation are strongly associated with ferroptosis resistance in NSCLC. Additionally, AIFM2 gene, which encodes ferroptosis suppressor protein 1 (FSP1), was identified as the gene most significantly correlated with ferroptosis resistance, followed by multiple NRF2 targets. We found that inhibition of NRF2 alone was not sufficient to reduce FSP1 protein levels and promote ferroptosis, whereas FSP1 inhibition effectively sensitized KEAP1-mutant NSCLC cells to ferroptosis. Furthermore, we found that combined inhibition of FSP1 and NRF2 induced ferroptosis more intensely. Our findings imply that FSP1 is a crucial suppressor of ferroptosis whose expression is partially dependent on NRF2 and that synergistically targeting both FSP1 and NRF2 may be a promising strategy for overcoming ferroptosis resistance in cancer.
Files in This Item:
T202305426.pdf Download
DOI
10.1038/s41419-023-06070-x
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Bae, Soo Han(배수한) ORCID logo https://orcid.org/0000-0002-8007-2906
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/196438
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