The influence of ATM, ATR, DNA-PK inhibitors on the cytotoxic and genotoxic effects of dibenzo[def,p]chrysene on human hepatocellular cancer cell line HepG2

Spryszyńska, Sylwia; Smok-Pieniążek, Anna; Ferlińska, Magdalena; Roszak, Joanna; Nocuń, Marek; Stępnik, Maciej

doi:10.1016/j.mrgentox.2015.07.008

Cited by 6 publications

(7 citation statements)

References 32 publications

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“…Cellular DNA is constantly challenged by either endogenous [reactive oxygen species (ROS)] or exogenous (UV) factors. To properly transmit the genetic information to the next generation, multiple delicate mechanisms underlying this event have been evolved in eukaryotic cells (1,2). DNA damage response (DDR) is such a crucial mechanism to ensure that genetic information is faithfully transmitted between generations.…”

Section: Introductionmentioning

confidence: 99%

“…In response to DNA damages, eukaryotic cells activate a complex signaling cascade to arrest the cell cycle for DNA repair. Dysregulation of DDR may result in severe disorders, such as tumorigenesis (1,(3)(4)(5). Therefore, it is critical to elucidate the mechanism of DDR in order to treat human diseases, such as cancer.…”

Section: Introductionmentioning

confidence: 99%

“…ATM and ATR respond to different types of DNA damage; ATM mainly responds to double-strand breaks (DSBs) while ATR mainly responds to replication stress and UV-induced pyrimidine dimers. According to previous studies (1,4,(6)(7)(8)(9), Ser/Thr kinase checkpoint kinase-1 (Chk1) and -2 (Chk2) are the two most thoroughly investigated substrates of ATR and ATM, respectively. In the situation of DNA damage, these pathways are able to activate p53, phosphorylate H2AX and other downstream pathways to activate the checkpoints of DNA damage, which eventually causes cell cycle arrest for DNA repair.…”

Section: Introductionmentioning

confidence: 99%

“…Defects in the ATR/Chk1 and ATM/Chk2 pathways are known to increase cancer risk (1,3). Once DSBs occur, ATM kinases can phosphorylate histone H2AX to form γH2AX foci at the DNA break sites.…”

Section: Introductionmentioning

confidence: 99%

“…Besides activating the formation of γH2AX nuclear foci, ATM can also induce cell cycle arrest through phosphorylation of its targets, p53 and Chk2. Numerous studies have demonstrated that phosphorylation of Chk2 can induce G2/M arrest by phosphorylating CDC25C, which prevents CDC25C from dephosphorylating CDC2 (or CDK1) (1)(2)(3)6,(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

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PTEN enhances G2/M arrest in etoposide-treated MCF-7 cells through activation of the ATM pathway

et al. 2016

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As an effective tumor suppressor, phosphatase and tensin homolog (PTEN) has attracted the increased attention of scientists. Recent studies have shown that PTEN plays unique roles in the DNA damage response (DDR) and can interact with the Chk1 pathway. However, little is known about how PTEN contributes to DDR through the ATM-Chk2 pathway. It is well-known that etoposide induces G2/M arrest in a variety of cell lines, including MCF-7 cells. The DNA damage-induced G2/M arrest results from the activation of protein kinase ataxia telangiectasia mutated (ATM), followed by the activation of Chk2 that subsequently inactivates CDC25C, resulting in G2/M arrest. In the present study, we assessed the contribution of PTEN to the etoposide-induced G2/M cell cycle arrest. PTEN was knocked down in MCF-7 cells by specific shRNA, and the effects of PTEN on the ATM-Chk2 pathway were investigated through various approaches. The results showed that knockdown of PTEN strongly antagonized ATM activation in response to etoposide treatment, and thereby reduced the phosphorylation level of ATM substrates, including H2AX, P53 and Chk2. Furthermore, depletion of PTEN reduced the etoposide-induced phosphorylation of CDC25C and strikingly compromised etoposide-induced G2/M arrest in the MCF-7 cells. Altogether, we demonstrated that PTEN plays a unique role in etoposide-induced G2/M arrest by facilitating the activation of the ATM pathway, and PTEN was required for the proper activation of checkpoints in response to DNA damage in MCF-7 cells.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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PTEN enhances G2/M arrest in etoposide-treated MCF-7 cells through activation of the ATM pathway

et al. 2016

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Determination of Metabolic Viability and Cell Mass Using a Tandem Resazurin/Sulforhodamine B Assay

et al. 2016

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The identification of rapid, reliable, and highly reproducible biological assays that can be standardized and routinely used in preclinical tests constitutes a promising approach to reducing drug discovery costs and time. This unit details a tandem, rapid, and reliable cell viability method for preliminary screening of chemical compounds. This assay measures metabolic activity and cell mass in the same cell sample using a dual resazurin/sulforhodamine B assay, eliminating the variation associated with cell seeding and excessive manipulations in assays that test different cell samples across plates. The procedure also reduces the amount of cells, test compound, and reagents required, as well as the time expended in conventional tests, thus resulting in a more confident prediction of toxic thresholds for the tested compounds. © 2016 by John Wiley & Sons, Inc.

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The effect of inhibitors of phosphatidylinositol 3-kinase-related kinases on dibenzo[def,p]chrysene genotoxicity measured by γH2AX levels and neutral comet assay in HepG2 human hepatocellular cancer cells

Kowalczyk

Roszak

Brodecki

et al. 2020

Toxicology in Vitro

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The influence of ATM, ATR, DNA-PK inhibitors on the cytotoxic and genotoxic effects of dibenzo[def,p]chrysene on human hepatocellular cancer cell line HepG2

Cited by 6 publications

References 32 publications

PTEN enhances G2/M arrest in etoposide-treated MCF-7 cells through activation of the ATM pathway

PTEN enhances G2/M arrest in etoposide-treated MCF-7 cells through activation of the ATM pathway

Determination of Metabolic Viability and Cell Mass Using a Tandem Resazurin/Sulforhodamine B Assay

The effect of inhibitors of phosphatidylinositol 3-kinase-related kinases on dibenzo[def,p]chrysene genotoxicity measured by γH2AX levels and neutral comet assay in HepG2 human hepatocellular cancer cells

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