Antioxidant agents transiently inhibit aneuploidy progression in Li‐Fraumeni cell strains

Kraniak, Janice M.; Abrams, Judith; Nowak, James E.; Tainsky, Michael A.

doi:10.1002/mc.20145

Cited by 8 publications

(6 citation statements)

References 72 publications

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“…It has been proposed that OS may contribute to carcinogenesis by increasing the frequency of genetic mutations and that ROS act as second messengers in multiple intracellular pathways, resulting in malignant transformation . Possible models that connect DNA aneuploidy with OS have been proposed . However, the role of OS in DNA aneuploidy remains controversial.…”

Section: Discussionmentioning

confidence: 99%

Contribution of BubR1 to oxidative stress‐induced aneuploidy in p53‐deficient cells

et al. 2013

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DNA aneuploidy is observed in various human tumors and is associated with the abnormal expression of spindle assembly checkpoint (SAC) proteins. Oxidative stress (OS) causes DNA damage and chromosome instability that may lead to carcinogenesis. OS is also suggested to contribute to an increase in aneuploid cells. However, it is not clear how OS is involved in the regulation of SAC and contributes to carcinogenesis associated with aneuploidy. Here we show that an oxidant (KBrO3) activated the p53 signaling pathway and suppressed the expression of SAC factors, BubR1, and Mad2, in human diploid fibroblast MRC5 cells. This suppression was dependent on functional p53 and reactive oxygen species. In p53 knockdown cells, KBrO3 did not suppress BubR1 and Mad2 expression and increased both binucleated cells and cells with >4N DNA content. BubR1 and not Mad2 downregulation suppressed KBrO3-induced binucleated cells and cells with >4N DNA content in p53 knockdown cells, suggesting that BubR1 contributes to enhanced polyploidization by a mechanism other than its SAC function. In analysis of 182 gastric cancer specimens, we found that BubR1 expression was significantly high when p53 was positively stained, which indicates loss of p53 function (P = 0.0019). Moreover, positive staining of p53 and high expression of BubR1 in tumors were significantly correlated with DNA aneuploidy (P = 0.0065). These observations suggest that p53 deficiency may lead to the failure of BubR1 downregulation by OS and that p53 deficiency and BubR1 accumulation could contribute to gastric carcinogenesis associated with aneuploidy.We found that OS could contribute to the emergence of polyploid cells when p53 was deficient in normal human fibroblast cells. Importantly, this polyploidization could be suppressed by downregulating the expression of one spindle assembly checkpoint factor, BubR1. We also found that p53 dysfunction and BubR1 accumulation strongly correlate with the extent of aneuploidy in gastric cancer specimen and our data suggest that p53 deficiency and BubR1 accumulation could contribute to gastric carcinogenesis associated with aneuploidy.

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Section: Discussionmentioning

confidence: 99%

Contribution of BubR1 to oxidative stress‐induced aneuploidy in p53‐deficient cells

et al. 2013

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“…In addition, ROS alone can induce p21 CIP/WAF1 expression even in the absence of p53, but to a lesser extent (Russo et al ., 1995). Treatment of three p53-deficient human fibroblast strains with five different antioxidants failed to inhibit their progression toward immortalization using intermediate markers such as anchorage-independent growth or cytogenetic abnormalities, although one antioxidant, oltipraz, was significantly effective in transiently delaying a shift to hyperdiploidy in all three cell strains (Kraniak et al ., 2006). Therefore, ROS inhibition alone is not sufficient to block the induction of senescence.…”

Section: Genomic Approaches To Identify Senescence/immortalization Gementioning

confidence: 99%

Critical pathways in cellular senescence and immortalization revealed by gene expression profiling

2008

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Bypassing cellular senescence and becoming immortal is a prerequisite step in the tumorigenic transformation of a cell. It has long been known that loss of a key tumor suppressor gene, such as p53, is necessary, but not sufficient, for spontaneous cellular immortalization. Therefore, there must be additional mutations and/or epigenetic alterations required for immortalization to occur. Early work on these processes included somatic cell genetic studies to estimate the number of senescence genes, and microcell-mediated transfer of chromosomes into immortalized cells to identify putative senescence-inducing genetic loci. These principal studies laid the foundation for the field of senescence/immortalization, but were labor intensive and the results were somewhat limited. The advent of gene expression profiling and bioinformatics analysis greatly facilitated the identification of genes and pathways that regulate cellular senescence/immortalization. In this review, we present the findings of several gene expression profiling studies and supporting functional data, where available. We identified universal genes regulating senescence/immortalization and found that the key regulator genes represented six pathways: the cell cycle pRB/p53, cytoskeletal, interferon-related, insulin growth factor-related, MAP kinase and oxidative stress pathway. The identification of the genes and pathways regulating senescence/immortalization could provide novel molecular targets for the treatment and/or prevention of cancer.

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“…Apart from inducing chromosomal abnormalities, polyploidy may also affect ROS levels as suggested by some literatures (Limoli et al, 2003;Kraniak et al, 2006;van de Wetering et al, 2008). Whether these ROS have any significant functional consequence on the polyploid cell and especially on its tumorigenic potential are not known at all.…”

mentioning

confidence: 99%

“…Some evidence suggests a possible relationship between ploidy and ROS levels. Antioxidant agents can inhibit aneuploidy progression (Kraniak et al, 2006), and overexpression of the antioxidant enzyme, manganese superoxide dismutase, inhibits chromosomal instability (van de Wetering et al, 2008). Oxidative damage to the liver is associated with an increase in the polyploid cell population (Gorla et al, 2001) and overexpression of antioxidant enzymes in mice decreases cellular ploidy during liver regeneration (Nakatani et al, 1997).…”

mentioning

confidence: 99%

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

Roh¹,

Meer²,

Abdulkadir³

2011

Journal Cellular Physiology

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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.

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Antioxidant agents transiently inhibit aneuploidy progression in Li‐Fraumeni cell strains

Cited by 8 publications

References 72 publications

Contribution of BubR1 to oxidative stress‐induced aneuploidy in p53‐deficient cells

Contribution of BubR1 to oxidative stress‐induced aneuploidy in p53‐deficient cells

Critical pathways in cellular senescence and immortalization revealed by gene expression profiling

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

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