A novel microtubule inhibitor promotes tumor ferroptosis by attenuating SLC7A11/GPX4 signaling

  • Cell Death Discov. 2023 Dec 13;9(1):453. doi: 10.1038/s41420-023-01713-6.
Nannan Ning  1  2 ,  Ziqi Shang  3 ,  Zhiping Liu  4 ,  Zhizhou Xia  5 ,  Yang Li  6 ,  Ruibao Ren  7  8 ,  Hongmei Wang  9 ,  Yi Zhang  10  11
Affiliations
  • 1. Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, China.
  • 2. Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan, China.
  • 3. Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 4. Center of Intelligent Medical Engineering, School of Control Science and Engineering, Shandong University, Jinan, China.
  • 5. Shanghai Institute of Hematology, National Research Center for Translational Medicine at Shanghai, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 6. Graduate School of Advanced Science and Engineering, Hiroshima University, Hiroshima, Japan.
  • 7. International Center for Aging and Cancer, Department of Hematology of The First Affiliated Hospital, Hainan Medical University, Haikou, China. [email protected].
  • 8. Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, National Research Center for Translational Medicine, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 9. Department of Pharmacology, School of Medicine, Southeast University, Nanjing, China. [email protected].
  • 10. Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, China. [email protected].
  • 11. Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan, China. [email protected].
PMID: 38086802 DOI: 10.1038/s41420-023-01713-6
Abstract

MP-HJ-1b is a novel microtubule inhibitor that we designed and reported previously. Ferroptosis is a newly identified type of nonapoptotic cell death induced by ferrous catalysis and lipid peroxidation. Here, transcriptomics, proteomics, and molecular docking analyses were combined to explore the novel effects of MP-HJ-1b on tumors. Both omics analyses suggested that MP-HJ-1b affects ribosomes, and we confirmed that it inhibits the ribosomal component proteins RPL35 and MRPL28. Colchicine was used as an analog, and the results showed that MP-HJ-1b and colchicine increased Reactive Oxygen Species and malondialdehyde levels and decreased reduced glutathione levels, suggesting that they promoted Ferroptosis in HeLa cells. Specifically, MP-HJ-1b downregulated SLC7A11 and GPX4 to enhance the classical pathway of Ferroptosis, while colchicine upregulated LC3A/B-II and enhanced Autophagy. Clinically, the serum concentrations of ferrous ions, reduced glutathione, and Hcy were higher in cervical Cancer patients than in healthy individuals. ALT, AST, Cho, HDL-C, and LDL-C levels were decreased in the serum of patients. Our study expands understanding of the way MP-HJ-1b promotes cell death and enriches research on microtubule inhibitors in the Ferroptosis field.

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