Radiation-induced upregulation of γ-glutamyltransferase in colon carcinoma cells is mediated through the Ras signal transduction pathway

The activity of γ-glutamyltransferase (GGT) is frequently upregulated in tumor cells after oxidative stress and may thus increase the availability of amino acids needed for biosynthesis of the antioxidant glutathione. As γ-radiation of tumor cells can result in oxidative stress, we investigated whet...

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Published in:Biochimica et biophysica acta Vol. 1760; no. 2; pp. 151 - 157
Main Authors: Pankiv, Serhiy, Møller, Seila, Bjørkøy, Geir, Moens, Ugo, Huseby, Nils-Erik
Format: Journal Article
Language:English
Published: Netherlands Elsevier B.V 01.02.2006
Subjects:
Animals
Apoptosis - radiation effects
Cell Line, Tumor
Colon carcinoma cell
Colonic Neoplasms - enzymology
Extracellular Signal-Regulated MAP Kinases - physiology
Gamma Rays
gamma-Glutamyltransferase - biosynthesis
gamma-Glutamyltransferase - radiation effects
Glutathione
Humans
MAP Kinase Kinase Kinases - physiology
Oxidative stress
Phosphatidylinositol 3-Kinases - physiology
Radioactive irradiation
ras Proteins - physiology
Rats
Reactive Oxygen Species - antagonists & inhibitors
Signal Transduction - physiology
Up-Regulation - radiation effects
γ-glutamyltransferase
Oxidative stress
PI-3K
JNK
MAPK
Radioactive irradiation
MEK
GGT
ROS
γ-glutamyltransferase
Colon carcinoma cell
GSH
ERK
Glutathione
ISSN:0304-4165, 0006-3002, 1872-8006
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Summary:The activity of γ-glutamyltransferase (GGT) is frequently upregulated in tumor cells after oxidative stress and may thus increase the availability of amino acids needed for biosynthesis of the antioxidant glutathione. As γ-radiation of tumor cells can result in oxidative stress, we investigated whether such treatments modulate the enzyme level in colon carcinoma CC531 cells. Radiation of these cells blocked cell proliferation, increased cellular size, initiated apoptosis and upregulated GGT activity and protein levels in a dose- and time-related manner. A slight but significant increase in the cellular level of reactive oxygen species (ROS) was found directly after radiation but appeared not to cause the GGT elevation. Thus, other mechanisms than cellular oxidative stress appear to be responsible for the radiation-induced upregulation of GGT. Stable transfection of activated Ras in a human colon carcinoma cell line expressing wild-type Ras resulted in an increased GGT level, while a reduced enzyme level was demonstrated in another cell line with constitutively activated Ras after stably transfection with a dominant-negative Ras mutant. Moreover, addition of specific protein kinase inhibitors that blocked downstream targets PI-3K and MEK1/2 of Ras, prior to and after radiation, attenuated the radiation-induced activation of GGT. These results support a role for Ras, being frequently activated after radiation, in regulating the level of GGT and also indicate that GGT participates in radioresistance.
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ISSN:0304-4165
0006-3002
1872-8006
DOI:10.1016/j.bbagen.2005.11.006