Signaling pathways involved in antioxidant control of glioma cell proliferation.
Tumor cells are able to survive and proliferate despite the higher-than-average level of reactive oxygen species (ROS) they exhibit. This is generally taken as a clue as to the implications of ROS in cell proliferation. In fact many mitogenic intracellular signaling pathways could be redox regulated, more particularly those involving tyrosine kinase receptors (RTK). In the present work we use N-acetylcysteine (NAC)-a well-known antioxidant molecule-to study the implications of cellular redox state on rat C6 glioma cell proliferation. NAC is shown to decrease glioma cell proliferation, inducing a cell cycle arrest in the G(0)/G(1) phase and markedly up-regulating p21 expression. A rapid, and glutathione-independent, decrease in intracellular oxidants was observed as well. NAC also lowers Akt activity, extracellular signal-regulated kinase 1/2, and the redox-sensitive transcription factor NF-kappaB, all of which are ROS related and seem to be in close connection with cell proliferation. NAC effects apparently relate to protein kinase C (PKC) activity because 100 nM TPA-a PKC activator-induces a partial blockage of the NAC antiproliferative effect. Bringing our results together, it seems that intracellular reduction of oxidants in C6 glioma cells can induce inhibition of cell proliferation by modulating RTK-related intracellular signaling pathways.
Martín
Vanesa
V
Departamento de Morfología y Biología Celular, Facultad de Medicina de la Universidad de Oviedo, c/Julian Clavería, 33006 Oviedo, Spain.
Herrera
Federico
F
García-Santos
Guillermo
G
Antolín
Isaac
I
Rodriguez-Blanco
Jezabel
J
Rodriguez
Carmen
C
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005910:Glioma / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
D000975:Antioxidants; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000111:Acetylcysteine