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Inhibition of proteasomal degradation of Mcl-1 by cobalt chloride suppresses cobalt chloride-induced apoptosis in HCT116 colorectal cancer cells

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Abstract

Cobalt promotes apoptosis in multiple cell systems, however, the molecular mechanisms that influence cobalt-induced apoptosis are not fully understood. We investigated mechanisms of cobalt chloride induced apoptosis in HCT116 colorectal cancer cells. Cobalt chloride induced dose dependent apoptosis in HCT116 cells (250–750 μM) which, at higher concentrations (500–750 μM), was associated with an increase in the expression of the Bcl-2-related Mcl-1 survival protein. Cobalt chloride caused the accumulation of higher molecular weight ubiquitin-conjugates of Mcl-1 in intact HCT116 cells and inhibited the activity of the trypsin-like site of the 20S proteasome in an in vitro assay. Although siRNA-mediated knockdown of Mcl-1 increased apoptosis in HCT116 cells, the combination of Mcl-1 siRNA and cobalt chloride induced very high levels of cell killing. Therefore, inhibition of the proteasome by cobalt chloride leads to the accumulation of Mcl-1 which acts to limit cobalt chloride induced apoptosis.

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Acknowledgements

We thank Drs. Luke Nolan and Serge Krysov for critical reading of the manuscript. We also thank Dr. Paul Townsend for assistance with the anoxia experiments and Drs. Ann Williams and Nadine Clemo for advice with the siRNA experiments. This work was supported by Cancer Research UK.

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Authors and Affiliations

  1. Cancer Research UK Clinical Centre, Cancer Sciences Division, University of Southampton School of Medicine, Southampton General Hospital, Southampton, SO16 6YD, UK

    Melanie Lee, Abigail Lapham, Matthew Brimmell, Helen Wilkinson & Graham Packham

  2. Cancer Research UK Clinical Centre, Somers Cancer Research Building (MP824), Cancer Sciences Division, University of Southampton School of Medicine, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK

    Graham Packham

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  1. Melanie Lee
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  2. Abigail Lapham
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Correspondence to Graham Packham.

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Lee, M., Lapham, A., Brimmell, M. et al. Inhibition of proteasomal degradation of Mcl-1 by cobalt chloride suppresses cobalt chloride-induced apoptosis in HCT116 colorectal cancer cells. Apoptosis 13, 972–982 (2008). https://doi.org/10.1007/s10495-008-0229-2

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