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.
MeSH terms
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Acetylcysteine / pharmacology
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CSK Tyrosine-Protein Kinase
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Cadherins / metabolism
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Cell Adhesion / drug effects
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Cell Adhesion / physiology
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Cell Adhesion Molecules / metabolism
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Cell Differentiation / drug effects
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Cell Differentiation / physiology*
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Cell Line, Tumor
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Colonic Neoplasms / metabolism
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Colonic Neoplasms / pathology*
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Cytoskeletal Proteins / metabolism
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Female
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Humans
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Keratinocytes / cytology
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Keratinocytes / drug effects
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Keratinocytes / metabolism
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Ovarian Neoplasms / metabolism
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Ovarian Neoplasms / pathology*
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Phosphotransferases / antagonists & inhibitors
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Phosphotransferases / metabolism
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Protein-Tyrosine Kinases
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Sulfhydryl Compounds / metabolism*
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Thymidine / metabolism
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Trans-Activators
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beta Catenin
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src-Family Kinases
Substances
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CTNNB1 protein, human
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Cadherins
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Cell Adhesion Molecules
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Cytoskeletal Proteins
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Proto-Oncogene Proteins
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Sulfhydryl Compounds
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Trans-Activators
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beta Catenin
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Phosphotransferases
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Protein-Tyrosine Kinases
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CSK Tyrosine-Protein Kinase
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src-Family Kinases
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CSK protein, human
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Thymidine
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Acetylcysteine