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

Journal Article

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 telomerase-transfected 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.

Full Text

Duke Authors

Cited Authors

  • Pritchard, DE; Ceryak, S; Ramsey, KE; O'Brien, TJ; Ha, L; Fornsaglio, JL; Stephan, DA; Patierno, SR

Published Date

  • November 2005

Published In

Volume / Issue

  • 279 / 1-2

Start / End Page

  • 169 - 181

PubMed ID

  • 16283527

Electronic International Standard Serial Number (EISSN)

  • 1573-4919

International Standard Serial Number (ISSN)

  • 0300-8177

Digital Object Identifier (DOI)

  • 10.1007/s11010-005-8292-2

Language

  • eng