Differentiation of normal and cancer cells induced by sulfhydryl reduction: biochemical and molecular mechanisms.
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.
Parasassi
T
T
Istituto di Neurobiologia e Medicina Molecolare, CNR, Viale Marx 15-43, 00137 Roma, Italy. t.parasassi@inmm.cnr.it
Brunelli
R
R
Bracci-Laudiero
L
L
Greco
G
G
Gustafsson
A C
AC
Krasnowska
E K
EK
Lundeberg
J
J
Lundeberg
T
T
Pittaluga
E
E
Romano
M C
MC
Serafino
A
A
D000111:Acetylcysteine / Q000494:pharmacology; D000081247:CSK Tyrosine-Protein Kinase; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D010770:Phosphotransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D013936:Thymidine / Q000378:metabolism; D015534:Trans-Activators; D051176:beta Catenin; D019061:src-Family Kinases
C495270:CTNNB1 protein, human; D015820:Cadherins; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D011518:Proto-Oncogene Proteins; D013438:Sulfhydryl Compounds; D015534:Trans-Activators; D051176:beta Catenin; D010770:Phosphotransferases; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D013936:Thymidine; D000111:Acetylcysteine