G-4 inhibits triple negative breast cancer by inducing cell apoptosis and promoting LCN2-dependent ferroptosis

[Display omitted] Compound G-4 is a derivate of cyclin-dependent kinase inhibitor Rocovitine and showed strong sensitivity to triple negative breast cancer (TNBC) cells. In this study, the antitumor activity, mechanism and possible targets of G-4 in TNBC were investigated. Flow cytometry and immunob...

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Published in:Biochemical pharmacology 2024-04, Vol.222, p.116077, Article 116077
Main Authors: Sun, Guoyang, Wang, Jinjin, Liu, Futao, Zhao, Cai, Cui, Shanshan, Wang, Zhaoyang, Liu, Zhen, Zhang, Qian, Xiang, Cen, Zhang, Yongmin, Galons, Herve, Yu, Peng, Teng, Yuou
Format: Article
Language:English
Subjects:
Apoptosis
Carrier Proteins - pharmacology
Cell Line, Tumor
ErbB Receptors - metabolism
Ferroptosis
G-4
Humans
Iron - metabolism
LCN2
Lipids - pharmacology
Lipocalin-2
Reactive Oxygen Species - metabolism
TNBC
Triple Negative Breast Neoplasms - metabolism
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Summary:[Display omitted] Compound G-4 is a derivate of cyclin-dependent kinase inhibitor Rocovitine and showed strong sensitivity to triple negative breast cancer (TNBC) cells. In this study, the antitumor activity, mechanism and possible targets of G-4 in TNBC were investigated. Flow cytometry and immunoblotting showed that G-4 not only arrested the S phase of the cell cycle, but also induced apoptosis in TNBC cells via the mitochondrial pathway through inhibiting epidermal growth factor receptor (EGFR), AKT and MAPK pathways. In addition, G-4 induced the iron-mutagenesis process in TNBC cells and down-regulated differentially expressed gene lipid carrier protein 2 (LCN2) by RNA-seq. Moreover, G-4 elevated levels of cytosolic reactive oxygen species (ROS), lipid ROS, Fe and malondialdehyde (MDA), but decreased levels of superoxide dismutase (SOD) and glutathione (GSH), consistent with the effects of iron-mutagenic agonists Erastin and RSL3, which were inhibited by the iron inhibitor ferrostatin-1 (Fer-1). Furthermore, a LCN2 knockdown cell model was established by siRNA transfection, the IC50 of G-4 was increased nearly 100-fold, accompanied by a trend of no ferroptosis characteristic index. The results indicated that G-4 suppressed the malignant phenotype of TNBC, induced apoptosis by inhibiting EGFR pathway and promoted LCN2-dependent ferroptosis.
ISSN:0006-2952
1873-2968
1873-2968
DOI:10.1016/j.bcp.2024.116077