Acidic pH induces topoisomerase II-mediated DNA damage

Xiao, Hai; Li, Tsai-Kun; Yang, Jin Ming; Liu, Leroy F.

doi:10.1073/pnas.0935978100

Cited by 73 publications

(36 citation statements)

References 40 publications

(37 reference statements)

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“…Consistent with this point of view, acidic pH has been shown to induce DNA breaks through poison of DNA topoisomerase II and substitute the tumor promotion effect of TPA in mouse skin. 45 In this study, our results suggest that MMR proteins play a downstream effecter of ROSinduced DNA damages (e.g. oxidative modification of nucleotides and DNA breaks) and lead to apoptotic DNA breakages and cell death.…”

Section: Discussionmentioning

confidence: 87%

DNA mismatch repair as an effector for promoting phorbol ester‐induced apoptotic DNA damage and cell killing: Implications in tumor promotion

Lin

Lee

et al. 2006

Intl Journal of Cancer

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Phorbol ester was known to activate protein kinase C (PKC) and exert numerous cellular effects, including proliferation, apoptosis, and oncogenic transformation. How phorbol ester stimulates both apoptosis and tumor promotion is not clear. Here DNA mismatch repair (MMR)-proficient human colon cancer cells (DLD-11Ch2; hMSH6 1 ) treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) undergo rapid cell death, which is significantly abolished by staurosporine (PKC inhibitor) or antioxidant, compared with the paired MMR-deficient (DLD-1; hMSH6 2 ) cells. Induction of reactive oxygen species (ROS) by TPA is shown to be one of downstream effectors required, but not sufficient, for cell killing as it is also observed in DLD-1 cells. Strikingly, DLD-11Ch2 cells selected for resistance to TPA are found to lose the expression of hMSH6. Treatment of TPA-resistant DLD-11Ch2 cells with 5-aza-2 0 -deoxycytidine, not only restores hMSH6 expression but also resensitizes TPA-resistant cells to TPA, suggesting that expression of hMSH6 is transcriptionally silenced by cytosine methylation confirmed directly by bisulfite sequencing. Knockdown hMSH6 or hPMS2 with siRNA in DLD-11Ch2 cells resulted in more resistant to TPA-induced cell killing, further suggesting that MMR proteins involve in TPA or ROS-induced cell killing. Results suggest that deficiency in MMR could promote tumorigenesis by inhibiting apoptotic responses to ROS-mediated DNA damages as ROS are continuously produced as a byproduct of normal metabolism. ' 2006 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 87%

DNA mismatch repair as an effector for promoting phorbol ester‐induced apoptotic DNA damage and cell killing: Implications in tumor promotion

Lin

Lee

et al. 2006

Intl Journal of Cancer

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“…Our findings that acid exposure can trigger those same pathways suggest that acid may be exerting direct genotoxic effects. Acid has been shown to cause DNA damage in Chinese hamster cells and in MDA-MB-231 breast cancer cells (30)(31)(32). Biopsies of metaplastic Barrett's epithelium exhibit high levels of DNA strand breaks and oxidative injury, and cultures of esophageal adenocarcinoma cells exposed to acid and bile acids develop DNA injuries (33)(34)(35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

“…Cyclin E-Cdk2 kinase activity was determined using histone H1 as the substrate for in vitro phosphorylation. The agarose bound with cyclin E-Cdk2 complexes was resuspended in 10 AL of kinase buffer containing 0.25 Ag/AL histone H1 (Roche), 40 Amol/L ATP (Sigma), and 0.5 ACi/AL [g- 32 P] ATP (Amersham Biosciences) and incubated at 30jC for 30 min. The kinase reaction was stopped by adding 3 AL of 4Â electrophoresis sample buffer, followed by boiling for 3 min at 95jC.…”

Section: Methodsmentioning

confidence: 99%

In Non-neoplastic Barrett's Epithelial Cells, Acid Exerts Early Antiproliferative Effects through Activation of the Chk2 Pathway

Zhang

Hormi–Carver

et al. 2007

Cancer Research

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Acid exerts pro-proliferative effects in Barrett's-associated esophageal adenocarcinoma cells. In non-neoplastic Barrett's epithelial (BAR-T) cells, in contrast, we have shown that acid exposure has antiproliferative effects. To explore our hypothesis that the acid-induced, antiproliferative effects are mediated by alterations in the proteins that regulate the G 1 -S cell cycle checkpoint, we exposed non-neoplastic Barrett's cells to acidic media (pH 4.0) and analyzed G 1 -S checkpoint proteins' expression, phosphorylation, and activity levels by Western blot. We studied acid effects on growth (by cell counts), proliferation (by flow cytometry and bromodeoxyuridine incorporation), cell viability (by trypan blue staining), and apoptosis (by annexin V staining), and we used caffeine and small interfering RNA to assess the effects of checkpoint kinase 2 (Chk2) inhibition on G 1 -S progression. Acid exposure significantly decreased cell numbers without affecting cell viability and with only a slight increase in apoptosis. Within 2 h of acid exposure, there was a delay in progression through the G 1 -S checkpoint that was associated with increased phosphorylation of Chk2, decreased levels of Cdc25A, and decreased activity of cyclin E-cyclin-dependent kinase 2; by 4 h, a continued delay at G 1 -S was associated with increased expression of p53 and p21. Caffeine and Chk2 siRNA abolished the acid-induced G 1 -S delay at 2 but not at 4 h. We conclude that acid exposure in non-neoplastic BAR-T cells causes early antiproliferative effects that are mediated by the activation of Chk2. Thus, we have elucidated a mechanism whereby acid can exert disparate effects on proliferation in neoplastic and non-neoplastic BAR-T cells.

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“…Finally, a change towards acidic pH as a possible DNA damage and nuclear condensation and cytotoxicity 54) inducer can be excluded, since the pH in all solutions, with or without xenobiotic and with or without antioxidant, was always in the neutral range (Table 4) and the presence of NAC in medium did not alter the DSB foci number relative to control (Fig. 2).…”

Section: Effects Of Monomers and Antioxidant On Nuclear Morphologymentioning

confidence: 99%

NAC ameliorates dental composite-induced DNA double-strand breaks and chromatin condensation

Styllou

Hickel

et al. 2017

Dental Materials Journal

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Released (co)monomers from dental composite components can induce DNA damage of which DNA double-strand breaks (DSBs) threaten genome integrity. Here, we tested whether the administration of the antioxidant N-acetylcysteine (NAC) is able to reduce the dental composite-induced DSBs in primary human gingiva fibroblasts. The dental composites Bis-GMA (bisphenol-Aglycerolate dimethacrylate), GMA (glycidyl methacrylate), HEMA (2-hydroxyethyl methacrylate) and TEGDMA (triethyleneglycol dimethacrylate) were found to induce co-localizing microscopic nuclear foci numbers of the DSB markers γ-H2AX and 53BP1 per cell in the order: GMA>Bis-GMA>TEGDMA>HEMA. Supplementation of (co)monomer-containing culture medium with NAC led to a significant reduction of resin-induced DSBs as well as to an amelioration of dental monomer-induced nuclear chromatin condensation in gingival fibroblasts. Thus, antioxidant treatment can reduce radical-induced chromatin and DNA damage and open avenues to mitigate genotoxic effects of dental composite compounds.

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Acidic pH induces topoisomerase II-mediated DNA damage

Cited by 73 publications

References 40 publications

DNA mismatch repair as an effector for promoting phorbol ester‐induced apoptotic DNA damage and cell killing: Implications in tumor promotion

DNA mismatch repair as an effector for promoting phorbol ester‐induced apoptotic DNA damage and cell killing: Implications in tumor promotion

In Non-neoplastic Barrett's Epithelial Cells, Acid Exerts Early Antiproliferative Effects through Activation of the Chk2 Pathway

NAC ameliorates dental composite-induced DNA double-strand breaks and chromatin condensation

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