Metabolic shift towards oxidative phosphorylation reduces cell-density-induced cancer-stem-cell-like characteristics in prostate cancer in vitro

Abstract

Background: Numerous cancer patients undergoing conventional cancer therapies such as radiotherapy, chemotherapy and surgical tumour removal face relapses several years or even decades later. This may be due to the presence of cancer stem cells (CSCs) which survived said therapies. In this study, we aimed to uncover the relationship between cell density and CSCs, and the role of the Warburg effect in regulating CSC-like characteristics. Method: A prostate cancer cell line, PC3, was used in this study. To investigate the Warburg effect effect and CSC-like characteristics in prostate cancer, we measured the expression levels of glycolysis and OXPHOS-related genes, and performed spheroid forming, cell viability and various glycolysis and OXPHOS-assays. Results: Increase cell density caused a metabolic shift from glycolysis to OXPHOS and higher CSC-like characteristics. However, the use of dichloroacetate (DCA), an inhibitor of the Warburg effect, significantly inhibited the cell density-induced metabolic shift and CSC-like characteristics. Conclusion: Changes in cell density strongly influenced the preferred metabolic pathway of prostate cancer cells, regulating their CSC-like characteristics. It is possible that DCA, an inhibitor of the Warburg effect, could be a novel drug used to treat CSCs by distinguishing Warburg effect, preventing future cancer relapses.

Transcending frontiers in prostate cancer: the role of oncometabolites on epigenetic regulation, CSCs, and tumor microenvironment to identify new therapeutic strategies

“…Recently, it was described in the prostatic PC-3 cell line that cell density shifts metabolism from glycolysis towards OXPHOS and induces a CSC-like phenotype. However, it seems that glycolysis and not OXPHOS is critical for CSC phenotype since dichloroacetate, a pyruvate dehydrogenase inhibitor, blocks the acquisition of CSC properties [ 166 ]. Nevertheless, this study was performed in vitro with only one cell line, requiring more studies to extract consistent conclusions.…”

Dichloroacetate for Cancer Treatment: Some Facts and Many Doubts

“…A very recent report [ 184 ] used a prostate cancer cell line (PC3) and showed that DCA can inhibit the cancer stem cell-like characteristics of the cells and strongly influence the metabolic pathway of the cells, causing a shift from glycolysis to oxidative phosphorylation. Their conclusion was that by inhibiting the Warburg effect, DCA may be useful in preventing future cancer relapses caused by cancer stem cells.…”