PMID- 35101731
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231020
IS  - 1872-8332 (Electronic)
IS  - 0169-5002 (Linking)
VI  - 165
DP  - 2022 Mar
TI  - Stratification of lung squamous cell carcinoma based on ferroptosis regulators: 
      Potential for new therapeutic strategies involving ferroptosis induction.
PG  - 82-90
LID - S0169-5002(22)00024-1 [pii]
LID - 10.1016/j.lungcan.2022.01.012 [doi]
AB  - OBJECTIVES: Lung squamous cell carcinoma (LSCC) exhibits poor response to 
      treatment compared with other lung cancer subtypes, resulting in worse prognosis. 
      Therefore, new therapeutic strategies are required for advanced LSCC. Ferroptosis 
      is a recently discovered nonapoptotic cell death caused by intracellular lipid 
      peroxidation that can bring about effective cell death in cancer cells resistant 
      to apoptosis. Hence, ferroptosis is a potential therapeutic strategy for 
      refractory cancer. MATERIALS AND METHODS: In this study, we performed 
      clinicopathological and molecular analyses on tumor specimens from 270 patients 
      with squamous cell lung cancer, focusing on the expression of glutathione 
      peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1), which are known 
      to be key regulators of ferroptosis, and the accumulation of 4-hydroxynoneral 
      (4-HNE), a lipid peroxidation marker. RESULTS: Immunohistochemistry revealed that 
      patients with low 4-HNE accumulation and low levels of GPX4 or FSP1 had 
      significantly worse prognoses than other patients (P = 0.001). This 
      stratification was an independent prognostic predictor (P = 0.003). A dramatic 
      cell death synergistic effect was observed on LSCC-derived LK-2 and EBC1 cells 
      treated with GPX4 and FSP1 inhibitors. This effect was completely inhibited by 
      treatment with the ferroptosis inhibitor. Notably, this was not the case in LK-2 
      cells treated with the apoptosis inhibitor, and in these cells, ferroptosis was 
      induced. CONCLUSION: Ferroptosis regulators GPX4 and FSP1 are associated with 
      lung squamous cell cancer cancer's prognosis. We present the clinicopathological 
      and molecular basis of novel therapeutic strategies for refractory LSCC.
CI  - Copyright (c) 2022 Elsevier B.V. All rights reserved.
FAU - Asakawa, Ayaka
AU  - Asakawa A
AD  - Department of Thoracic Surgery, Graduate School of Medical and Dental Sciences, 
      Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
FAU - Kawade, Genji
AU  - Kawade G
AD  - Department of Comprehensive Pathology, Graduate School of Medical and Dental 
      Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
FAU - Kurata, Morito
AU  - Kurata M
AD  - Department of Comprehensive Pathology, Graduate School of Medical and Dental 
      Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
FAU - Fukuda, Sho
AU  - Fukuda S
AD  - Department of Comprehensive Pathology, Graduate School of Medical and Dental 
      Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
FAU - Onishi, Iichiroh
AU  - Onishi I
AD  - Department of Comprehensive Pathology, Graduate School of Medical and Dental 
      Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
FAU - Kinowaki, Yuko
AU  - Kinowaki Y
AD  - Department of Comprehensive Pathology, Graduate School of Medical and Dental 
      Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
FAU - Ishibashi, Sachiko
AU  - Ishibashi S
AD  - Department of Comprehensive Pathology, Graduate School of Medical and Dental 
      Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
FAU - Ikeda, Masumi
AU  - Ikeda M
AD  - Department of Comprehensive Pathology, Graduate School of Medical and Dental 
      Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
FAU - Watabe, Shiori
AU  - Watabe S
AD  - Department of Comprehensive Pathology, Graduate School of Medical and Dental 
      Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
FAU - Kobayashi, Masashi
AU  - Kobayashi M
AD  - Department of Thoracic Surgery, Graduate School of Medical and Dental Sciences, 
      Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
FAU - Ishibashi, Hironori
AU  - Ishibashi H
AD  - Department of Thoracic Surgery, Graduate School of Medical and Dental Sciences, 
      Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
FAU - Okubo, Kenichi
AU  - Okubo K
AD  - Department of Thoracic Surgery, Graduate School of Medical and Dental Sciences, 
      Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
FAU - Kitagawa, Masanobu
AU  - Kitagawa M
AD  - Department of Comprehensive Pathology, Graduate School of Medical and Dental 
      Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
FAU - Yamamoto, Kouhei
AU  - Yamamoto K
AD  - Department of Comprehensive Pathology, Graduate School of Medical and Dental 
      Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan. Electronic 
      address: yamamoto.pth2@tmd.ac.jp.
LA  - eng
PT  - Journal Article
DEP - 20220124
PL  - Ireland
TA  - Lung Cancer
JT  - Lung cancer (Amsterdam, Netherlands)
JID - 8800805
SB  - IM
OTO - NOTNLM
OT  - Ferroptosis
OT  - Lipid peroxidation
OT  - Lung squamous cell carcinoma
OT  - Nonapoptotic cell death
OT  - Refractive cancer
OT  - Therapy
EDAT- 2022/02/02 06:00
MHDA- 2022/02/02 06:01
CRDT- 2022/02/01 06:02
PHST- 2021/07/04 00:00 [received]
PHST- 2021/08/20 00:00 [revised]
PHST- 2022/01/19 00:00 [accepted]
PHST- 2022/02/02 06:01 [medline]
PHST- 2022/02/02 06:00 [pubmed]
PHST- 2022/02/01 06:02 [entrez]
AID - S0169-5002(22)00024-1 [pii]
AID - 10.1016/j.lungcan.2022.01.012 [doi]
PST - ppublish
SO  - Lung Cancer. 2022 Mar;165:82-90. doi: 10.1016/j.lungcan.2022.01.012. Epub 2022 
      Jan 24.