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Selenium activates p53 and p38 pathways and induces caspase-independent cell death in cervical cancer cells

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Abstract

The mechanisms of sodium selenite-induced cell death in cervical carcinoma cells were studied during 24 h of exposure in the HeLa Hep-2 cell line. Selenite at the employed concentrations of 5 and 50 μmol/L produced time- and dose-dependent suppression of DNA synthesis and induced DNA damage which resulted in phosphorylation of histone H2A.X. These effects were influenced by pretreatment of cells with the SOD/catalase mimetic MnTMPyP or glutathione-depleting buthionine sulfoximine, suggesting the significant role of selenite-generated oxidative stress. Following the DNA damage, selenite activated p53-dependent pathway as evidenced by the appearance of phosphorylated p53 and accumulation of p21 in the treated cells. Concomitantly, selenite activated p38 pathway but its effect on JNK was very weak. p53- and p38-dependent signaling led to the accumulation of Bax protein, which was preventable by specific inhibitors of p38 (SB 203580) and p53 (Pifithrin-α). Mitochondria in selenite-treated cells changed their dynamics (shape and localization) and released AIF and Smac/Diablo, which initiated caspase-independent apoptosis as confirmed by the caspase-3 activity assay and the low effect of caspase inhibitors z-DEVD-fmk and z-VAD-fmk on cell death. We conclude that selenite induces caspase-independent apoptosis in cervical carcinoma cells mostly by oxidative stress-mediated activation of p53 and p38 pathways, but other selenite-mediated effects, in particular mitochondria-specific ones, are also involved.

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Abbreviations

AIF:

apoptosis-inducing factor

BA:

bonkrekic acid

BrdU:

bromodeoxyuridine

BSO:

buthionine sulfoximine

Chaps:

3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid

DAPI:

4′,6-diamidino-2-phenylindole

DCF:

dichlorofluorescein

DCFH/DA:

2′,7′-dichlorofluorescein diacetate

DMEM:

Dulbecco’s modified Eagle’s medium

DTNB:

5,5′-dithio-bis(2-nitrobenzoic acid)

DTT:

dithiotreitol

EDTA:

ethylenediaminetetraacetic acid

GR:

glutathione reductase

GSH:

reduced glutathione

GSSH:

oxidized glutathione

JNK:

Jun N-terminal kinase

MnTMPyP:

Mn(III)tetrakis (1-methyl-4-pyridyl) porphyrin

Pifithrin-α:

(2-(2-imino-4,5,6,7-tetrahydrobenzothiazol-3-yl)-1-p-tolylethanone, HBr)

ROS:

reactive oxygen species

SB:

203580 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole

selenite:

sodium selenite

SP600125:

anthra[1,9-cd]pyrazol-6(2H)-one 1,9-pyrazoloanthrone

z-DEVD-fmk:

Z-Asp-Glu-Val-Asp-fluoromethylketone

z-VAD-fmk:

benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone

β-NADPH:

beta-nicotinamide-adenine dinucleotide phosphate

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Acknowledgment

This work was supported by Ministry of Education Research Project MSM 0021620820.

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Authors and Affiliations

  1. Department of Medical Biology and Genetics, Charles University in Prague, Faculty of Medicine in Hradec Králové, Šimkova 870, 500 38, Hradec Králové, Czech Republic

    E. Rudolf & M. Červinka

  2. Department of Rheumatology and Clinical Pharmacology, 2nd Internal Clinic, Faculty Teaching Hospital in Hradec Králové, Hradec Králové, Czech Republic

    K. Rudolf

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Correspondence to E. Rudolf.

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Rudolf, E., Rudolf, K. & Červinka, M. Selenium activates p53 and p38 pathways and induces caspase-independent cell death in cervical cancer cells. Cell Biol Toxicol 24, 123–141 (2008). https://doi.org/10.1007/s10565-007-9022-1

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