TY - JOUR
T1 - Protein kinase C activation by anthracyclines in Swiss 3T3 cells
AU - Lanzi, C.
AU - Gambetta, R. A.
AU - Perego, P.
AU - Banfi, P.
AU - Franzi, A.
AU - Guazzoni, L.
AU - Zumino, F.
PY - 1991
Y1 - 1991
N2 - The effects of the anti-cancer anthracyclines doxorubicin and daunorubicin on the activity of protein kinase C (PKC) were examined in intact Swiss 3T3 cells. The 2 drugs stimulated the phosphorylation of an 80K phosphoprotein found to be identical to that generated in response to the PKC activator 12-O-tetradecanoylphorbol-13-acetate as indicated by gel electrophoresis and peptide mapping. The effect of doxorubicin was dose-dependent in the range 10-5 to 10-3 M and was not associated with a detectable translocation of PKC activity from cytosol to the cell membrane. Doxorubicin and daunorubicin were found to increase the incorporation of phosphate into phosphatidic acid, phosphatidylinositol 4-monophosphate and phosphatidyl inositol 4,5-bisphosphate. In addition, the anthracyclines induced a rise in inositol phosphates, thus indicating a stimulation of the breakdown of phosphoinositides. These data are consistent with an indirect mechanism of PKC activation by anthracyclines. We propose that diacylglycerol, which is derived from the hydrolysis of phospholipids, (including the phosphoinositides), by activation of phospholipases, could mediate PKC activation. The described effects, involving cell-signal-transducing pathways, emphasize a new aspect of the cellular actions of these anti-tumor agents.
AB - The effects of the anti-cancer anthracyclines doxorubicin and daunorubicin on the activity of protein kinase C (PKC) were examined in intact Swiss 3T3 cells. The 2 drugs stimulated the phosphorylation of an 80K phosphoprotein found to be identical to that generated in response to the PKC activator 12-O-tetradecanoylphorbol-13-acetate as indicated by gel electrophoresis and peptide mapping. The effect of doxorubicin was dose-dependent in the range 10-5 to 10-3 M and was not associated with a detectable translocation of PKC activity from cytosol to the cell membrane. Doxorubicin and daunorubicin were found to increase the incorporation of phosphate into phosphatidic acid, phosphatidylinositol 4-monophosphate and phosphatidyl inositol 4,5-bisphosphate. In addition, the anthracyclines induced a rise in inositol phosphates, thus indicating a stimulation of the breakdown of phosphoinositides. These data are consistent with an indirect mechanism of PKC activation by anthracyclines. We propose that diacylglycerol, which is derived from the hydrolysis of phospholipids, (including the phosphoinositides), by activation of phospholipases, could mediate PKC activation. The described effects, involving cell-signal-transducing pathways, emphasize a new aspect of the cellular actions of these anti-tumor agents.
UR - http://www.scopus.com/inward/record.url?scp=0025970669&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0025970669&partnerID=8YFLogxK
U2 - 10.1002/ijc.2910470124
DO - 10.1002/ijc.2910470124
M3 - Article
C2 - 1845961
AN - SCOPUS:0025970669
VL - 47
SP - 136
EP - 142
JO - International Journal of Cancer
JF - International Journal of Cancer
SN - 0020-7136
IS - 1
ER -