Tumorigenic polyploid cells contain elevated ROS and ARE selectively targeted by antioxidant treatment

Abstract

Polyploidy has been linked to tumorigenicity mainly due to the chromosomal aberrations. Elevated reactive oxygen species (ROS) generation, on the other hand, has also been associated with oncogenic transformation in most cancer cells. However, a possible link between ploidy and ROS is largely unexplored. Here we have exemined the role of ROS in the tumorigenicity of polyploid cells. We show that polyploid prostate and mammary epithelial cells contain higher levels of ROS due to their higher mitochondrial contents. ROS levels and mitochondrial mass are also higher in dihydrocytochalasin B (DCB)-induced polyploid cells, suggesting that higher levels of ROS observed in polyploid cell can occur due to cytokinesis failure. Interestingly, polyploid cells were more sensitive to the inhibitory effect of the antioxidant, N-Acetyl-L-cysteine (NAC), than control diploid cells. Treatment of polyploid/diploid cells with NAC led to the selective elimination of polyploid cells over time and abrogated the tumorigenicity of polyploid cells. This effect was partially mediated via the Akt signaling pathway. We next explored a possible role for ROS in promoting chromosomal instability by analyzing the effects of ROS on the mitotic stage of the cell cycle. Enhancing ROS levels by treating cells with hydrogen peroxide delayed not only entry into and but also exit from mitosis. Furthermore, increasing ROS levels significantly increased taxol resistance. Our results indicated that increased ROS in polyploid cells can contribute to tumorigenicity and highlight the therapeutic potential of antioxidants by selectively targeting the tumorigenic polyploid cells and by reversing taxol resistance.

Aurora A Kinase Inhibitor AKI603 Induces Cellular Senescence in Chronic Myeloid Leukemia Cells Harboring T315I Mutation

“…S3A). We and other previously reported that the level of glycolytic metabolism and the ROS level were significantly increased in the polyploidy cells162829. ROS is considered to be one of the important inducers of senescence3031, thus we examined whether ROS production was involved in the occurrence of senescence in KBM5 and KBM5-T315I cells.…”

Inhibition of mTOR Pathway Sensitizes Acute Myeloid Leukemia Cells to Aurora Inhibitors by Suppression of Glycolytic Metabolism

“…In the study of comparison in the whole genomic transcripts of polyploidy and nonpolyploidy decidual cells in mouse, genes involved in metabolic process were upregulated (23). In addition, immortalized nontumorigenic human prostate and mammary epithelial cells which overexpressed pim-1, could gradually convert to polyploidy cells, with increase of reactive oxygen species (ROS) level (31). In aneuploid cells, the metabolic properties were also altered with increased glucose and glutamine consumption (32).…”

Hydrogen peroxide fuels aging, inflammation, cancer metabolism and metastasis

“…[126][127][128][129][130][131][132][133][134][135][136][137] As such, hydrogen peroxide may be directly involved in the earliest tumor initiating events. 126,127,137,138 In accordance with this notion, addition of catalase to the extracellular tissue culture media is indeed sufficient to prevent or dramatically delay the onset of cell transformation and genomic instability, when normal cells are presented with an oncogenic stimulus.…”