Abstract
We examined the morphological, biochemical and molecular outcome of a nonspecific sulfhydryl reduction in cells, obtained by supplementation of N-acetyl-L-cysteine (NAC) in a 0.1–10?mM concentration range. In human normal primary keratinocytes and in colon and ovary carcinoma cells we obtained evidences for: (i) a dose-dependent inhibition of proliferation without toxicity or apoptosis; (ii) a transition from a proliferative mesenchymal morphology to cell-specific differentiated structures; (iii) a noticeable increase in cell–cell and cell–substratum junctions; (iv) a relocation of the oncogenic β-catenin at the cell–cell junctions; (v) inhibition of microtubules aggregation; (vi) upregulation of differentiation-related genes including p53, heat shock protein 27 gene, N-myc downstream-regulated gene 1, E-cadherin, and downregulation of cyclooxygenase-2; (vii) inhibition of c-Src tyrosine kinase. In conclusion, a thiol reduction devoid of toxicity as that operated by NAC apparently leads to terminal differentiation of normal and cancer cells through a pleiade of converging mechanisms, many of which are targets of the recently developed differentiation therapy.
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Abbreviations
- HSP27:
-
heat shock protein 27 gene
- NAC:
-
N-acetyl-L-cysteine
- NHEK:
-
normal human epidermal keratinocytes
- NDRG1:
-
N-myc downstream-regulated gene 1
- NSAIDs:
-
non-steroidal anti-inflammatory drugs
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Acknowledgements
We thank Giuseppe Starace for performing the flow cytometry measurements and data analysis. We also thank Graziella Costa for her excellent technical assistance. This work was supported by Nactilus AB, Malmö, Sweden (TP, LB-L, GG, EKK, MCR) and by the Swedish Cancer Foundation (ACG, JL).
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Parasassi, T., Brunelli, R., Bracci-Laudiero, L. et al. Differentiation of normal and cancer cells induced by sulfhydryl reduction: biochemical and molecular mechanisms. Cell Death Differ 12, 1285–1296 (2005). https://doi.org/10.1038/sj.cdd.4401663
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DOI: https://doi.org/10.1038/sj.cdd.4401663
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