Abstract
Sorafenib is a tyrosine kinase inhibitor that shows anti-tumour effects against various cancers including gastric cancer (GC). However, the clinical application of sorafenib is often hampered by drug resistance. Sirtuins 6 (SIRT6) is a member of the Sirtuin family of NAD (+)-dependent enzymes that are critically involved in various biological activities. This study presents that SIRT6 silencing overcomes sorafenib resistance by promoting ferroptosis, which is a novel form of cell death. Mechanistically, SIRT6 inhibition led to the inactivation of the Keap1/Nrf2 signalling pathway and downregulation of GPX4. The overexpression of GPX4 or activation of Keap1/Nrf2 reverses the effects of the downregulation of SIRT6 on sorafenib-induced ferroptosis. Thus, targeting the SIRT6/Keap1/Nrf2/GPX4 signalling pathway may be a potential strategy for overcoming sorafenib resistance in GC.
Keywords:
Ferroptosis; GPX4; Gastric cancer; Keap1/Nrf2; SIRT6.
Copyright © 2021 Elsevier Inc. All rights reserved.
MeSH terms
-
Blotting, Western
-
Cell Line, Tumor
-
Cell Proliferation / drug effects
-
Cell Proliferation / genetics
-
Cell Survival / drug effects
-
Cell Survival / genetics
-
Drug Resistance, Neoplasm / drug effects
-
Drug Resistance, Neoplasm / genetics*
-
Ferroptosis / drug effects
-
Ferroptosis / genetics*
-
Gene Expression Regulation, Neoplastic
-
Humans
-
Kelch-Like ECH-Associated Protein 1 / genetics
-
Kelch-Like ECH-Associated Protein 1 / metabolism
-
NF-E2-Related Factor 2 / genetics
-
NF-E2-Related Factor 2 / metabolism
-
Phospholipid Hydroperoxide Glutathione Peroxidase / genetics
-
Phospholipid Hydroperoxide Glutathione Peroxidase / metabolism
-
Protein Kinase Inhibitors / pharmacology
-
RNA Interference*
-
Reverse Transcriptase Polymerase Chain Reaction
-
Signal Transduction / genetics
-
Sirtuins / genetics*
-
Sirtuins / metabolism
-
Sorafenib / pharmacology*
-
Stomach Neoplasms / genetics*
-
Stomach Neoplasms / metabolism
-
Stomach Neoplasms / pathology
Substances
-
KEAP1 protein, human
-
Kelch-Like ECH-Associated Protein 1
-
NF-E2-Related Factor 2
-
NFE2L2 protein, human
-
Protein Kinase Inhibitors
-
Sorafenib
-
Phospholipid Hydroperoxide Glutathione Peroxidase
-
SIRT6 protein, human
-
Sirtuins