Activation of protein kinase C by 1-beta-D-arabinofuranosylcytosine conjugates of phospholipid.
1-beta-D-arabinofuranosylcytosine (ara-C) conjugates of phospholipid were shown to be highly antineoplastic against various tumor cells. In this study, we report that these conjugates are potent activators of protein kinase C (PKC, EC) in vitro. Although required Ca2+, PKC activation by the conjugates occurred even in the absence of phospholipid and diacylglycerol. Among the conjugates, 1-beta-D-arabino-furanosylcytosine 5'-diphosphate-rac-1-O-octadecyl-2-O-palmitoylglycerol [(ara-CDP-DL-PBA); ara-C conjugate of ether phospholipid], was employed to investigate its mode of activation, since ether phospholipid has been reported to be a regulator of the PKC. When PKC was activated by ara-CDP-DL-PBA, diacylglycerol enhanced its activity with 3-fold reduction of an apparent Ka value for ara-CDP-DL-PBA and no change in the Vmax. During the PKC activation by phosphatidylserine, ara-CDP-DL-PBA exhibited a synergistic effect on the activation. Studies on the relationship between the structures of ara-CDP-DL-PBA and their effects on PKC activity showed that phosphate group of ether lipid was important for its activation of PKC, and that conjugation of ara-C and ether lipid further enhanced the enzyme activity. These results suggest that the ara-C conjugate of phospholipid activates PKC in a co-operative manner with diacylglycerol and/or phosphatidylserine, however, the exact mechanism of the antineoplastic effect of ara-CDP-DL-PBA through PKC activation still remains speculative.
Lee
Kee-Ho
KH
Laboratory of Molecular Oncology, Korea Institute of Radiological and Medical Sciences, Nowon-Ku, Seoul 139-240, Korea.
Jung
Yu-Jin
YJ
Hong
Chung-Il
CI
Cho
Myung-Haing
MH
Bai
Dong-Hoon
DH
Kim
Sang-Hoon
SH
Choi
Kang-Yell
KY
Yu
Ju-Hyun
JH
Kim
Chang-Min
CM
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D003561:Cytarabine / Q000737:chemistry* / Q000494:pharmacology; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004075:Diglycerides / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D007700:Kinetics; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D010718:Phosphatidylserines / Q000737:chemistry / Q000494:pharmacology; D010743:Phospholipids / Q000737:chemistry* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011479:Protamines / Q000378:metabolism; D011493:Protein Kinase C / Q000302:isolation & purification / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D004075:Diglycerides; D008565:Membrane Proteins; D010718:Phosphatidylserines; D010743:Phospholipids; D011479:Protamines; D003561:Cytarabine; D011493:Protein Kinase C