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Recombinant heat shock protein 27 (HSP27/HSPB1) protects against cadmium-induced oxidative stress and toxicity in human cervical cancer cells

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Cell Stress and Chaperones Aims and scope

Abstract

Cadmium (Cd) is a carcinogen with several well-described toxicological effects in humans, but its molecular mechanisms are still not fully understood. Overexpression of heat shock protein 27 (HSP27/HSPB1)—a multifunctional protein chaperone—has been shown to protect cells from oxidative damage and apoptosis triggered by Cd exposure. The aims of this work were to investigate the potential use of extracellular recombinant HSP27 to prevent/counteract Cd-induced cellular toxicity and to evaluate if peroxynitrite was involved in the development of Cd-induced toxicity. Here, we report that the harmful effects of Cd correlated with changes in oxidative stress markers: upregulation of reactive oxygen species, reduction in nitric oxide (NO) bioavailability, increment in lipid peroxidation, peroxynitrite (PN), and protein nitration; intracellular HSP27 was reduced. Treatments with Cd (100 μM) for 24 h or with the peroxynitrite donor, SIN-1, decreased HSP27 levels (~50%), suggesting that PN formation is responsible for the reduction of HSP27. Pre-treatments of the cells either with Nω-nitro-l-arginine methyl ester hydrochloride (L-NAME) (a pharmacological inhibitor of NO synthase) or with recombinant HSP27 (rHSP27) attenuated the disruption of the cellular metabolism induced by Cd, increasing in a 55 and 52%, respectively, the cell viability measured by CCK-8. Cd induced necrotic cell death pathways, although apoptosis was also activated; pre-treatment with L-NAME or rHSP27 mitigated cell death. Our findings show for the first time a direct relationship between Cd-induced toxicity and PN production and a role for rHSP27 as a potential therapeutic agent that may counteract Cd toxicity.

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Acknowledgements

We are grateful to Dr. Youngmi Kim (Department of Chemistry, Institute of Nanosensor and Biotechnology, Dankook University, Korea) for the gift of the fluorescent probe-1 for the peroxynitrite determination.

This work was supported by operating grants jointly funded by the Canadian Institute for Health Research (CIHR) and Medtronic Canada (ISO 110836) as well as the Heart and Stroke Foundation of Canada (G-13-0001599). CIHR and Medtronic also collectively funded a peer-reviewed research chair [grant IRC 57093] to EO. The National Research Council of Argentina (CONICET) is also thanked for financial support [PIP 11220110100836 DAS 30844] to DRC.

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Authors and Affiliations

  1. Oncology Laboratory at the Institute of Experimental Medicine and Biology of Cuyo (IMBECU), CCT CONICET Mendoza, Av. Ruiz Leal S/N Parque Gral. San Martin, CP 5500, Mendoza, CP, Argentina

    Daiana G. Alvarez-Olmedo, Daniel R. Ciocca & Mariel A. Fanelli

  2. Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, Foothills Medical Centre, University of Calgary, Room C823, 1403—29th Street NW, Calgary, AB, T2N 2T9, Canada

    Daiana G. Alvarez-Olmedo, Geremy A. Koumbadinga, Chunhua Shi, Zarah Batulan & Edward R. O’Brien

  3. Department of Biochemistry and Biological Sciences, Faculty of Chemistry, Biochemistry, and Pharmacy, National University of San Luis, IMIBIO-SL, CONICET, San Luis, Argentina

    Veronica S. Biaggio & Nidia N. Gómez

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  1. Daiana G. Alvarez-Olmedo
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  2. Veronica S. Biaggio
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Correspondence to Mariel A. Fanelli or Edward R. O’Brien.

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Fanelli and O’Brien contributed equally to this work.

Electronic supplementary material

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Supplementary figure 1

Peroxynitrite production A) HeLa cells pre-loaded with probe-1 were exposed either to Cd, SIN-1 (positive control, donor of NO and superoxide) or 10 μM H2O2 (which induces superoxide species but not peroxynitrite). The spectra were obtained each minute during a period of 30 min and fluorescence intensity at 540 nm was measured with excitation at 430 nm. B-C) Untreated control HeLa cells or pre-treated with 500 μM L-NAME were pre-loaded with probe 1 and then exposed to 5 μM Cd (B) or 100 μM Cd (C) to assay peroxynitrite production. In all cases the graph values represent the means of three independent experiments ±SD (n=6). (GIF 51 kb)

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Supplementary figure 2

HSP27 content in HeLa cells. A) Western blott of HeLa cells Control (line 1), treated with 100 μM Cd during 24h (line 2), L-NAME and then Cd (line 3), pre-treated with rHSP2 or rC1 and then Cd (line 4-5 respectively). B) Optical density of HSP27/beta-actin expression. The graph values represent the means of three independent experiments ±SD (* p< 0,05; ** p< 0,01; *** p< 0,001). (GIF 39.5 kb)

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Supplementary figure 3

Peroxynitrite production and cellular effects. (GIF 66.2 kb)

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Supplementary figure 4

Viability of HeLa cells measured as metabolic activity with CCK-8. A) HeLa cells were grown in 96 well plates and then the cells were exposed to the indicated doses of Cd during different times (3-24 h). B) HeLa pScr cells were stable transfected with a scramble plasmid, selected as indicate in methodology grown in 96 well plate with hygronomycin for 24 hr and then exposed to the indicated doses of Cd in serum-hygronomycin free media. C) HeLa p762 cells (downregulation for HSP27 in a 50%), were grown in 96 well plate with hygronomycin for 24 hr and then exposed to the indicated doses of Cd in serum-hygronomycin free media. All the values are representative of the means of three independent experiments ±SD (* p< 0,05; ** p< 0,01; *** p< 0,001; n=6 for each data point). (GIF 41.4 kb)

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Alvarez-Olmedo, D.G., Biaggio, V.S., Koumbadinga, G.A. et al. Recombinant heat shock protein 27 (HSP27/HSPB1) protects against cadmium-induced oxidative stress and toxicity in human cervical cancer cells. Cell Stress and Chaperones 22, 357–369 (2017). https://doi.org/10.1007/s12192-017-0768-y

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  • DOI: https://doi.org/10.1007/s12192-017-0768-y

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