2. Academic Validation
  3. Gambogenic acid inhibits proliferation and ferroptosis by targeting the miR-1291/FOXA2 and AMPKα/SLC7A11/GPX4 axis in colorectal cancer

Gambogenic acid inhibits proliferation and ferroptosis by targeting the miR-1291/FOXA2 and AMPKα/SLC7A11/GPX4 axis in colorectal cancer

  • Cell Biol Int. 2023 Jul 20. doi: 10.1002/cbin.12072.
Xiaoqi Ma 1,  Midie Xu 2 3 4,  Xing Zhang 1,  Xin Wang 2,  Kexin Su 1,  Zihang Xu 5,  Xiaoyu Wang 1 6,  Yifu Yang 1
Affiliations

Affiliations

  • 1 Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China.
  • 2 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, P.R. China.
  • 3 Department of Medical Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
  • 4 Institute of Pathology, Fudan University, Shanghai, P.R. China.
  • 5 School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China.
  • 6 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China.
PMID: 37471707 DOI: 10.1002/cbin.12072
Abstract

The present study aims to investigate the mechanism of the nature compound gambogenic acid (GNA) on the Apoptosis and Ferroptosis in colorectal Cancer (CRC). The effect of GNA on the proliferation of CRC cell lines were detected by MTT and clonogenic assay. The xenograft tumor model was established, and the inhibition effect of GNA were evaluated by observing the tumor growth. The endoplasmic reticulum (ER) of HCT116 was observed by using the ER tracker. The TargrtScan database was used to predict the miRNA binding sites. The level of miRNA with GNA treatment was explored by real-time quantitative PCR. The effect of Ferroptosis were evaluated by detect the expression of Reactive Oxygen Species (ROS), intracellular ferrous iron (Fe2+ ), malondialdehyde (MDA), glutathione (GSH), subunit solute carrier family 7 member 11 (SLC7A11), Glutathione Peroxidase (GPX)4, transferrin, and ferritin by Western blot. GNA isolated from gamboge can inhibit the growth and proliferation of CRC cell lines in a concentration-dependent manner. GNA activated ER stress by upregulating miR-1291, and miR-1291 targeted the forkhead box protein A2 (FOXA2). GNA also induced ROS production and mediated the Fenton reaction by activating transferrin to increase Fe2+ , thus inducing Ferroptosis. In addition, GNA could induce Ferroptosis through the depletion of GSH and GPX4. Furthermore, GNA treatment regulated iron metabolism by activating AMPKα/SLC7A11/GPX4 signaling. In conclusion, GNA activated ER stress via miR-1291 and induced Ferroptosis in CRC cells and might be a new inducer of Ferroptosis, which can expand the efficacy of chemotherapy drugs.

Keywords

endoplasmic reticulum stress; intracellular ferrous iron; miRNA.

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