PMID- 34157442
OWN - NLM
STAT- MEDLINE
DCOM- 20211118
LR  - 20240226
IS  - 1090-2104 (Electronic)
IS  - 0006-291X (Linking)
VI  - 567
DP  - 2021 Aug 27
TI  - Inhibition of GPX4 or mTOR overcomes resistance to Lapatinib via promoting 
      ferroptosis in NSCLC cells.
PG  - 154-160
LID - S0006-291X(21)00972-4 [pii]
LID - 10.1016/j.bbrc.2021.06.051 [doi]
AB  - Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase and 
      mutations in EGFR is a major driver force of lung cancer. EGFR tyrosine kinase 
      inhibitors (TKIs) are group of promising agents to treat cancer patients with 
      EGFR mutations. However, the application of TKIs is often hampered by the 
      development of drug-resistance. In the present study, we studied the role of 
      Glutathione peroxidase 4 (GPX4) and mammalian target of rapamycin (mTOR) in 
      regulation of lung cancer cells response to Lapatinib (Lap). Lap resistant NSCLC 
      cells A549/Lap and H1944/Lap were created and GPX4 was knockdown by lentivirus 
      shGPX4. Change of cell viabilities and cell death were measured by MTT and flow 
      cytometry, respectively. ROS, MDA, GSH and Fe(2+) were detected by commercial 
      kits. Xenograft mice was used to assay the in vivo effects of GPX4 on the 
      sensitivity of Lap. We found that GPX4 and mTORC1 signalling was upregulated in 
      Lap resistant NSCLC cells when compared to Lap sensitive NSCLC cells. 
      Mechanistically, upregulation of GPX4 was due to enhanced activation of mTORC1 in 
      Lap resistant NSCLC cells. Inhibition of mTORC1 led to the downregulation of GPX4 
      which promoted Lap induced ferroptosis as evidenced by increase of ROS, MDA, Fe 
      (2+) and decrease of GSH. Rescue experiments confirmed the role of GPX4 in 
      regulation of Lap induced ferroptosis. In vivo experiments also indicated that 
      silencing of GPX4 enhanced the anticancer effect of Lap via promoting 
      ferroptosis. Overall, targeting GPX4 might be a potential strategy to enhance 
      antitumor effects of Lap.
CI  - Copyright (c) 2021 Elsevier Inc. All rights reserved.
FAU - Ni, Jiangwei
AU  - Ni J
AD  - Department of Thoracic Surgery, The First Affiliated Hospital of Wenzhou Medical 
      University, Wenzhou, Zhejiang, China.
FAU - Chen, Kun
AU  - Chen K
AD  - Department of Thoracic Surgery, The First Affiliated Hospital of Wenzhou Medical 
      University, Wenzhou, Zhejiang, China.
FAU - Zhang, Jiandong
AU  - Zhang J
AD  - Department of Thoracic Surgery, The First Affiliated Hospital of Wenzhou Medical 
      University, Wenzhou, Zhejiang, China.
FAU - Zhang, Xiang
AU  - Zhang X
AD  - Department of Thoracic Surgery, The First Affiliated Hospital of Wenzhou Medical 
      University, Wenzhou, Zhejiang, China. Electronic address: 
      zx15868755708@outlook.com.
LA  - eng
PT  - Journal Article
DEP - 20210620
PL  - United States
TA  - Biochem Biophys Res Commun
JT  - Biochemical and biophysical research communications
JID - 0372516
RN  - 0 (Antineoplastic Agents)
RN  - 0VUA21238F (Lapatinib)
RN  - EC 1.11.1.12 (Phospholipid Hydroperoxide Glutathione Peroxidase)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - A549 Cells
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Carcinoma, Non-Small-Cell Lung/*drug therapy/genetics/metabolism
MH  - Drug Resistance, Neoplasm
MH  - Ferroptosis/drug effects
MH  - Gene Silencing
MH  - Humans
MH  - Lapatinib/*pharmacology
MH  - Lung Neoplasms/*drug therapy/genetics/metabolism
MH  - Male
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Phospholipid Hydroperoxide Glutathione Peroxidase/genetics/*metabolism
MH  - TOR Serine-Threonine Kinases/genetics/*metabolism
MH  - Mice
OTO - NOTNLM
OT  - Ferroptosis
OT  - GPX4
OT  - Lapatinib
OT  - Non-small cell lung cancer
OT  - mTOR
COIS- Declaration of competing interest None.
EDAT- 2021/06/23 06:00
MHDA- 2021/11/19 06:00
CRDT- 2021/06/22 20:13
PHST- 2021/06/12 00:00 [received]
PHST- 2021/06/14 00:00 [accepted]
PHST- 2021/06/23 06:00 [pubmed]
PHST- 2021/11/19 06:00 [medline]
PHST- 2021/06/22 20:13 [entrez]
AID - S0006-291X(21)00972-4 [pii]
AID - 10.1016/j.bbrc.2021.06.051 [doi]
PST - ppublish
SO  - Biochem Biophys Res Commun. 2021 Aug 27;567:154-160. doi: 
      10.1016/j.bbrc.2021.06.051. Epub 2021 Jun 20.