1. Academic Validation
  2. 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: tyo201485@tust.edu.cn.
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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