Abstract
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.
Highlights
Metabolic reprogramming is a central hallmark of cancer.[1]
We previously found that zinc promoted apoptosis and cell cycle arrest induced by Pmp53.21,22
Li found that p53 induces growth inhibition by modulating SIRT3 deacetylase activity in EJ‐p53 cells.31In addition, Abigail found that ACO2 and superoxide dismutase 2 (SOD2) can form a co‐regulated multi‐protein complex in mouse heart mitochondria.[32]
Summary
Metabolic reprogramming is a central hallmark of cancer.[1]. Multiple studies have shown that the canceration and development of many cancers are accompanied by metabolic remodeling.[2,3] Normal prostate cells have the uniquely specialized function of accumulating and secreting extremely high levels of citrate, the main component of prostatic fluid.[5,6] The citrate production activity of prostate cells is achieved by cellular accumulation of high levels of zinc that inhibit citrate oxidation. We previously found that zinc promoted apoptosis and cell cycle arrest induced by Pmp[53] (a plasmid containing both MDM2 small interfering RNA and the wild‐type p53 gene).[21,22] Further research has shown that p53 plays an important role in the regulation of redox state and metabolism in the tumor cells.[23,24] The SIRT3 deacetylase regulates the transcription and deacetylation of superoxide dismutase 2 (SOD2) to decrease ROS levels.[27,28] Guo found that activated p53 inhibits SOD2 expression, leading to increased ROS levels in hepatocellular carcinoma.[30] Li found that p53 induces growth inhibition by modulating SIRT3 deacetylase activity in EJ‐p53 cells.31In addition, Abigail found that ACO2 and SOD2 can form a co‐regulated multi‐protein complex in mouse heart mitochondria.[32] these results suggest the possibility of a p53‐SIRT3‐SOD2‐ROS axis that may function in the regulation of ACO2. Targeting ACO2 through zinc and p53 may provide a new strategy for the therapy of prostate cancer
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