2. Academic Validation
  3. G-4 inhibits triple negative breast cancer by inducing cell apoptosis and promoting LCN2-dependent ferroptosis

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

  • Biochem Pharmacol. 2024 Feb 21:222:116077. doi: 10.1016/j.bcp.2024.116077.
Guoyang Sun 1,  Jinjin Wang 1,  Futao Liu 1,  Cai Zhao 1,  Shanshan Cui 1,  Zhaoyang Wang 1,  Zhen Liu 1,  Qian Zhang 1,  Cen Xiang 1,  Yongmin Zhang 2,  Herve Galons 3,  Peng Yu 1,  Yuou Teng 4
Affiliations

Affiliations

  • 1 China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin 300457, China.
  • 2 Sorbonne Université, Institut Parisien de Chimie Moléculaire, UMR8232 CNRS, 4 place Jussieu, 75005 Paris, France.
  • 3 China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin 300457, China; Université Paris Cité, 4, avenue de l'Observatoire 75006 Paris, France.
  • 4 China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin 300457, China. Electronic address: [email protected].
PMID: 38395264 DOI: 10.1016/j.bcp.2024.116077
Abstract

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.

Keywords

Apoptosis; Ferroptosis; G-4; LCN2; TNBC.

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