Beryllium sulfate induces p21 CDKN1A expression and a senescence-like cell cycle arrest in susceptible cancer cell types.
In fibroblasts, beryllium salt causes activation of the p53 transcription factor and induction of a senescence-like state. It is not known whether Be(2+) 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, BeSO(4) produced a G(0)/G(1)-phase cell cycle arrest and increased expression of senescence-associated β-galactosidase, an enzymatic marker of senescence. BeSO(4) 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. BeSO(4) inhibited A172 growth with an IC(50) = 4.7 μM in a 6-day proliferation assay. In contrast, BeSO(4) had no effect on RKO cells, even though Be(2+) uptake was similar for the two cell types. This differential responsiveness marks BeSO(4) 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 BeSO(4). Conversely, BeSO(4) 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 BeSO(4) is distinct from the DNA damage response pathway, even though both ultimately converge on p53 and p21.
Gorjala
Priyatham
P
Department of Chemistry, University of Nevada Las Vegas, 4505 Maryland Parkway, Las Vegas, NV 89154-4003, USA.
Gary
Ronald K
RK
D001608:Beryllium / Q000378:metabolism / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000503:physiopathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis*; D016158:Genes, p53 / Q000187:drug effects; D005909:Glioblastoma / Q000503:physiopathology; D006801:Humans; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D001616:beta-Galactosidase / Q000096:biosynthesis
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; C020711:beryllium sulfate; D001616:beta-Galactosidase; D001608:Beryllium