Zinc cooperates with p53 to inhibit the activity of mitochondrial aconitase through reactive oxygen species accumulation

Cancer Med. 2019 May;8(5):2462-2473. doi: 10.1002/cam4.2130. Epub 2019 Apr 10.


Metabolic reprogramming is a central hallmark of cancer. Therefore, targeting metabolism may provide an effective strategy for identifying promising drug targets for cancer treatment. In prostate cancer, cells undergo metabolic transformation from zinc-accumulating, citrate-producing cells to citrate-oxidizing malignant cells with lower zinc levels and higher mitochondrial aconitase (ACO2) activity. ACO2 is a Krebs cycle enzyme that converts citrate to isocitrate and is sensitive to reactive oxygen species (ROS)-mediated damage. In this study, we found that the expression of ACO2 is positively correlated with the malignancy of prostate cancer. Both zinc and p53 can lead to an increase in ROS. ACO2 can be a target for remodeling metabolism by sensing changes in the ROS levels of prostate cancer. Our results indicate that targeting ACO2 through zinc and p53 can change prostate cancer metabolism, and thus provides a potential new therapeutic strategy for prostate cancer.

Keywords: ROS; mitochondrial aconitase; p53; zinc.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aconitate Hydratase / metabolism*
  • Animals
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Male
  • Mice
  • PC-3 Cells
  • Paclitaxel / administration & dosage*
  • Paclitaxel / pharmacology
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Reactive Oxygen Species / metabolism*
  • Tumor Suppressor Protein p53 / administration & dosage*
  • Tumor Suppressor Protein p53 / pharmacology
  • Up-Regulation / drug effects
  • Xenograft Model Antitumor Assays
  • Zinc / administration & dosage*
  • Zinc / pharmacology


  • Reactive Oxygen Species
  • Tumor Suppressor Protein p53
  • ACO2 protein, human
  • Aconitate Hydratase
  • Zinc
  • Paclitaxel