1. Differentiation of normal and cancer cells induced by sulfhydryl reduction: biochemical and molecular mechanisms.
- Author
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Parasassi T, Brunelli R, Bracci-Laudiero L, Greco G, Gustafsson AC, Krasnowska EK, Lundeberg J, Lundeberg T, Pittaluga E, Romano MC, and Serafino A
- Subjects
- Acetylcysteine pharmacology, CSK Tyrosine-Protein Kinase, Cadherins metabolism, Cell Adhesion drug effects, Cell Adhesion physiology, Cell Adhesion Molecules metabolism, Cell Differentiation drug effects, Cell Line, Tumor, Colonic Neoplasms metabolism, Cytoskeletal Proteins metabolism, Female, Humans, Keratinocytes cytology, Keratinocytes drug effects, Keratinocytes metabolism, Ovarian Neoplasms metabolism, Phosphotransferases antagonists & inhibitors, Phosphotransferases metabolism, Protein-Tyrosine Kinases, Proto-Oncogene Proteins antagonists & inhibitors, Proto-Oncogene Proteins metabolism, Reverse Transcriptase Polymerase Chain Reaction, Thymidine metabolism, Trans-Activators, beta Catenin, src-Family Kinases, Cell Differentiation physiology, Colonic Neoplasms pathology, Ovarian Neoplasms pathology, Sulfhydryl Compounds metabolism
- 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 beta-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.
- Published
- 2005
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