Derivation and Study of Human Epithelial Cell Lines Resistant to Killing by Chromium Trioxide

Son, Kyu-Yeol; Zhang, Mingjun; Rucobo, Eliana; Nwaigwe, Dwight; Montgomery, Frederick C.; Leffert, Hyam L.

doi:10.1080/15287390490447304

Cited by 3 publications

(4 citation statements)

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“…Such a mechanism has been shown in human epithelial cell lines resistant to killing by CrO 3 [50], and has been observed with other toxic metals such as arsenic, platinum, and antimony [51,52]. The resistance of the B-5Cr cells to both Cr (VI)-and H 2 O 2 -induced cell death would suggest that the mechanism was not a function of alteration of cellular Cr(VI) accumulation.…”

Section: Discussionmentioning

confidence: 91%

Resistance to apoptosis, increased growth potential, and altered gene expression in cells that survived genotoxic hexavalent chromium [Cr(VI)] exposure

et al. 2005

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Certain hexavalent chromium [Cr(VI)] compounds are known genotoxic respiratory carcinogens, which induce apoptosis as a predominant mode of cell death. Selection of cells that are resistant to apoptosis may be a factor in tumour progression. We developed sub-populations of telomerasetransfected human fibroblasts (BJ-hTERT) that survived a 99% clonogenically lethal exposure to Cr (VI) (B-5Cr). B-5Cr cells were markedly resistant to apoptosis induced by several agents and exhibited increased clonogenic survival, especially at apoptogenic doses. B-5Cr cells did not exhibit altered cellular uptake of Cr(VI) and retained a normal p53 response to Cr(VI) exposure. We conducted large-scale gene expression analysis at different time-points after a secondary genotoxic Cr(VI) insult in B-5Cr and BJ-hTERT cells using Affymetrix Genechip® human genome arrays. Cr (VI) exposure led to differential regulation of many genes, which affect a diverse set of cellular activities such as transcription, signal transduction, stress response, cell adhesion, DNA repair, apoptosis and cell cycle modulation. We compared Cr(VI)-induced altered gene expression in the B-5Cr cells to that in the parental cells and identified 223, 147 and 204 genes with at least a two-fold difference in expression at 4, 8 and 18 h after exposure, respectively. Cluster analysis by gene function revealed altered expression of genes involved in apoptosis, cell cycle regulation and DNA repair. Our data suggest an alteration in gene expression that may favor cell survival and/or incomplete DNA repair after genotoxic exposure. Selection of cells with altered expression of these genes may constitute the early stages of tumour progression.

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Section: Discussionmentioning

confidence: 91%

Resistance to apoptosis, increased growth potential, and altered gene expression in cells that survived genotoxic hexavalent chromium [Cr(VI)] exposure

et al. 2005

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“…In vitro models of cellular death-resistance generated via long-term, chronic, and slowly escalating exposure doses are advantageous when studying the role of altered transport and intracellular pharmacodynamics in response to cellular genotoxic stress [37-40]. However, our system is unique in that it models initial molecular events that occur in a normal cell that survived a single, acute, initiating genotoxic challenge.…”

Section: Discussionmentioning

confidence: 99%

Acquisition of mitochondrial dysregulation and resistance to mitochondrial-mediated apoptosis after genotoxic insult in normal human fibroblasts: A possible model for early stage carcinogenesis

Nickens

Han

Shandilya

et al. 2012

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Acquisition of death-resistance is critical in the evolution of neoplasia. Our aim was to model the early stages of carcinogenesis by examining intracellular alterations in cells that have acquired apoptosis-resistance after exposure to a complex genotoxin. We previously generated sub-populations of BJ-hTERT human diploid fibroblasts, which have acquired death-resistance following exposure to hexavalent chromium [Cr(VI)], a broad-spectrum genotoxicant. Long-term exposure to certain forms of Cr(VI) is associated with respiratory carcinogenesis. Here, we report on the death-sensitivity of subclonal populations derived from clonogenic survivors of BJ-hTERT cells treated with 5 μM Cr(VI) (DR1, DR2), or selected by dilution-based cloning without treatment (CC1). Following Cr(VI) treatment, CC1 cells downregulated expression of the anti-apoptotic protein Bcl-2 and exhibited extensive expression of cleaved caspase 3. In contrast, the DR cells exhibited no cleaved caspase 3 expression and maintained expression of Bcl-2 following recovery from 24 h Cr(VI) exposure. The DR cells also exhibited attenuated mitochondrial-membrane depolarization and mitochondrial retention of cytochrome c and SMAC/DIABLO following Cr(VI) exposure. The DR cells exhibited less basal mtDNA damage, as compared to CC1 cells, which correlates with intrinsic (non-induced) death-resistance. Notably, there was no difference in p53 protein expression before or after treatment among all cell lines. Taken together, our data suggest the presence of more resilient mitochondria in death-resistant cells, and that death-resistance can be acquired in normal human cells early after genotoxin exposure. We postulate that resistance to mitochondrial-mediated cell death and mitochondrial dysregulation may be an initial phenotypic alteration observed in early stage carcinogenesis.

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“…Using human 293 embryonic kidney cells made resistant to Cr(VI) (as assessed by toxicity assays), the authors also showed no difference in cellular morphology between the Cr(VI)-resistant and -sensitive cell lines. These authors reported a significant reduction in Cr(VI) uptake in the resistant cells as measured by the uptake of radiolabeled 51 Cr [128]. The Cr(VI)- resistant cells displayed a greater sensitivity to density-dependent growth inhibition and were found to grow at a slower rate than the wild-type sensitive cells, in the absence of Cr(VI).…”

Section: Chromium Genotoxicity: a Double-edged Swordmentioning

confidence: 99%

“…Moreover, these studies revealed that the observed resistant phenotype was also Cr(VI)-specific, as the Cr(VI)-resistant cells were sensitive to treatment with nickel sulfate. Notably, one draw back of this study of Cr(VI) resistance is that the wild-type cells used to create the resistant subclones, were tumorigenic when injected into nude mice [128]. This implies that these cells may already harbor a genetic predisposition to dysregulation of DNA damage response pathways, leading to Cr(VI) resistance.…”

Section: Chromium Genotoxicity: a Double-edged Swordmentioning

confidence: 99%

Chromium genotoxicity: A double-edged sword

Nickens¹,

Patierno²,

Ceryak³

2010

Chemico-Biological Interactions

321

175

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Certain forms of hexavalent chromium [Cr(VI)] are known respiratory carcinogens that induce a broad spectrum of DNA damage. Cr(VI)-carcinogenesis may be initiated or promoted through several mechanistic processes including, the intracellular metabolic reduction of Cr(VI) producing chromium species capable of interacting with DNA to yield genotoxic and mutagenic effects, Cr(VI)-induced inflammatory/immunological responses, and alteration of survival signaling pathways. Cr(VI) enters the cell through nonspecific anion channels, and is metabolically reduced by agents including ascorbate, glutathione, and cysteine to Cr(V), Cr(IV), and Cr(III). Cr(III) has a weak membrane permeability capacity and is unable to cross the cell membrane, thereby trapping it within the cell where it can bind to DNA and produce genetic damage leading to genomic instability. Structural genetic lesions produced by the intracellular reduction of Cr(VI) include DNA adducts, DNA strand breaks, DNA-protein crosslinks, oxidized bases, abasic sites, and DNA inter-and intrastrand crosslinks. The damage induced by Cr(VI) can lead to dysfunctional DNA replication and transcription, aberrant cell cycle checkpoints, dysregulated DNA repair mechanisms, microsatelite instability, inflammatory responses, and the disruption of key regulatory gene networks responsible for the balance of cell survival and cell death, which may all play an important role in Cr(VI) carcinogenesis. Several lines of evidence have indicated that neoplastic progression is a result of consecutive genetic/epigenetic changes that provide cellular survival advantages, and ultimately lead to the conversion of normal human cells to malignant cancer cells. This review is based on studies that provide a glimpse into Cr(VI) carcinogenicity via mechanisms including Cr(VI)-induced death-resistance, the involvement of DNA repair mechanisms in survival after chromium exposure, and the activation of survival signaling cascades in response to Cr(VI) genotoxicity.

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Derivation and Study of Human Epithelial Cell Lines Resistant to Killing by Chromium Trioxide

Cited by 3 publications

References 46 publications

Resistance to apoptosis, increased growth potential, and altered gene expression in cells that survived genotoxic hexavalent chromium [Cr(VI)] exposure

Resistance to apoptosis, increased growth potential, and altered gene expression in cells that survived genotoxic hexavalent chromium [Cr(VI)] exposure

Acquisition of mitochondrial dysregulation and resistance to mitochondrial-mediated apoptosis after genotoxic insult in normal human fibroblasts: A possible model for early stage carcinogenesis

Chromium genotoxicity: A double-edged sword

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