Induction of cyclin-dependent kinase inhibitors and G(1) prolongation by the chemopreventive agent N-acetylcysteine.
Cyclin-dependent kinase (cdk) inhibitors, such as p16(INK4a) and p21(WAF1/CIP1), often inhibit G(1) cyclin kinases and result in G(1) arrest. It has been suggested that p21(WAF1/CIP1) may also play a role in other chemopreventive activities such as DNA repair, slowdown of DNA replication and induction of cellular differentiation. In this report we demonstrate that the antioxidant N-acetylcysteine (NAC), a well-known chemopreventive agent, induces p16(INK4a) and p21(WAF1/CIP1) gene expression and prolongs cell-cycle transition through G(1) phase. A portion of the G(1) arrest by NAC is governed by p16(INK4a); it is independent of p53. NAC's usual mechanism of increasing intracellular glutathione level is not required for the G(1) arrest. An antioxidant whose action is limited to scavenging radicals, Trolox, does not induce G(1) arrest. Taken together, these results suggest a potential novel molecular basis for chemoprevention by NAC.
Liu
M
M
Department of Therapeutic Radiology and Department of Genetics, Yale University School of Medicine, New Haven, CT 06520-8040, USA.
Wikonkal
N M
NM
Brash
D E
DE
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis* / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019942:Genes, p16 / Q000187:drug effects*; D005978:Glutathione / Q000502:physiology; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D010212:Papilloma / Q000473:pathology; D012878:Skin Neoplasms / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D016588:Anticarcinogenic Agents; D000975:Antioxidants; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D002839:Chromans; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016166:Free Radical Scavengers; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53; D005978:Glutathione; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; D000111:Acetylcysteine