Carcinogenic potential and genomic instability of beryllium sulphate in BALB/c-3T3 cells

Keshava, Nagalakshmi; Zhou, Gu; Spruill, Michelle; Ensell, Mang; Ong, Tong-man

doi:10.1007/978-1-4615-0793-2_9

Cited by 5 publications

(6 citation statements)

References 16 publications

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“…BeSO 4 is non-clastogenic to Chinese hamster lung cells at 3.5 mM and lower (Ashby et al 1990). On the other hand, 0.5–2.0 mM BeSO 4 causes some increase in the transformation frequency of BALB/c-3T3 cells (Keshava et al 2001), but these concentrations are orders of magnitude greater than needed to cause cell cycle arrest in susceptible cell types. Thus, the carcinogen literature is probably not relevant to the low concentration cytostatic effects reported here.…”

Section: Discussionmentioning

confidence: 99%

Beryllium sulfate induces p21 CDKN1A expression and a senescence-like cell cycle arrest in susceptible cancer cell types

Gorjala

Gary

2010

Biometals

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In fibroblasts, beryllium salt causes activation of the p53 transcription factor and induction of a senescence-like state. It is not known whether Be2+ can affect the proliferation of cancer cells, which are generally unsusceptible to senescence. A172 glioblastoma and RKO colon carcinoma cell lines each have wildtype p53, so these cell types have the potential to be responsive to agents that activate p53. In A172 cells, BeSO4 produced a G0/G1-phase cell cycle arrest and increased expression of senescence-associated β-galactosidase, an enzymatic marker of senescence. BeSO4 caused phosphorylation of serine-15 of p53, accumulation of p53 protein, and expression of p21, the cyclin-dependent kinase inhibitor that is prominent during senescence. BeSO4 inhibited A172 growth with an IC50 = 4.7 µM in a 6-day proliferation assay. In contrast, BeSO4 had no effect on RKO cells, even though Be2+ uptake was similar for the two cell types. This differential responsiveness marks BeSO4 as a reagent capable of activating a separable branch of the p53 signaling network. A172 and RKO cells are known to exhibit p53-dependent upregulation of p21 in response to DNA damage. The RKO cells produced high levels of p21 when exposed to DNA damaging agents, yet failed to express p21 when treated with BeSO4. Conversely, BeSO4 did not cause DNA damage in A172 cells, yet it was a potent inducer of p21 expression. These observations indicate that the growth control pathway affected by BeSO4 is distinct from the DNA damage response pathway, even though both ultimately converge on p53 and p21.

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Section: Discussionmentioning

confidence: 99%

Beryllium sulfate induces p21 CDKN1A expression and a senescence-like cell cycle arrest in susceptible cancer cell types

Gorjala

Gary

2010

Biometals

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“…Based on the recent progress of understanding the genetic events of carcinogenesis, of cancer invasion, progression, and metastasis, more recently leading genes of these processes (the so-called proto-oncogenes and tumor suppressor genes) have attracted much attention as targets of mutagenic/carcinogenic attack. Transcriptional activation of proto-oncogenes (c-fos, c-jun, c-myc) was induced in BALB/c-3T3 and nude mouse tumorigenesis models by cadmium (Joseph et al 2001), and even amplification of the oncogenes K-ras and c-jun, in addition to genomic instability, was attained in similar experiments using beryllium sulfate (Keshava et al 2001). Examination of the effects of As, Cd, Cr, and Pb on the gene expression regulated by a battery of 13 different promoters in recombinant HepG2 cells revealed, among others, also induction of fos and the tumor suppressor p53 response element (Tully et al 2000).…”

Section: Genetic and Cellular Mechanismsmentioning

confidence: 97%

Mutagenicity, Carcinogenicity, and Teratogenicity

Gebhart¹

2004

Elements and Their Compounds in the Environment

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“…At high concentrations, beryllium is somewhat carcinogenic to mammalian cells (Gordon and Bowser, 2003). For example, 560 M BeSO 4 causes a 14-fold increase in BALB/c-3T3 cell trans- formation frequency compared with the spontaneous transformation rate (Keshava et al, 2001). The effects of Be 2ϩ on the immune system are complex.…”

Section: Discussionmentioning

confidence: 99%

Beryllium Induces Premature Senescence in Human Fibroblasts

Coates

Lehnert

Sharma³

et al. 2007

J Pharmacol Exp Ther

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After cells have completed a sufficient number of cell divisions, they exit the cell cycle and enter replicative senescence. Here, we report that beryllium causes proliferation arrest with premature expression of the principal markers of senescence. After young presenescent human fibroblasts were treated with 3 M BeSO 4 for 24 h, p21 cyclin-dependent kinase inhibitor mRNA increased by Ͼ200%. Longer periods of exposure caused mRNA and protein levels to increase for both p21 and p16(Ink4a), a senescence regulator that prevents pRb-mediated cell cycle progression. BeSO 4 also caused dose-dependent induction of senescence-associated ␤-galactosidase activity (SA-␤-gal). Untreated cells had 48 relative fluorescence units (RFU)/g/h of SA-␤-gal, whereas 3 M BeSO 4 caused activity to increase to 84 RFU/g/h. In chromatin immunoprecipitation experiments, BeSO 4 caused p53 protein to associate with its DNA binding site in the promoter region of the p21 gene, indicating that p53 transcriptional activity is responsible for the large increase in p21 mRNA elicited by beryllium. Forced expression of human telomerase reverse transcriptase (hTERT) rendered HFL-1 cells incapable of normal replicative senescence. However, there was no difference in the responsiveness of normal HFL-1 fibroblasts (IC 50 ϭ 1.9 M) and hTERT-immortalized cells (IC 50 ϭ 1.7 M) to BeSO 4 in a 9-day proliferation assay. The effects of beryllium resemble those of histone deacetylase-inhibiting drugs, which also cause large increases in p21. However, beryllium produced no changes in histone acetylation, suggesting that Be 2ϩ acts as a novel and potent pharmacological inducer of premature senescence.

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Carcinogenic potential and genomic instability of beryllium sulphate in BALB/c-3T3 cells

Cited by 5 publications

References 16 publications

Beryllium sulfate induces p21 CDKN1A expression and a senescence-like cell cycle arrest in susceptible cancer cell types

Beryllium sulfate induces p21 CDKN1A expression and a senescence-like cell cycle arrest in susceptible cancer cell types

Mutagenicity, Carcinogenicity, and Teratogenicity

Beryllium Induces Premature Senescence in Human Fibroblasts

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