Effects of suramin-related and other clinically therapeutic polyanions on protein kinase C activity.
The mechanism of the antineoplastic effects of suramin may involve interference with signal transduction, but in general is not well understood. We examined several polyanions to determine their effects on the kinase activity of the protein kinase C (PKC) beta1 and other PKC isoforms. Similar to suramin, a phosphorothioate oligodeoxynucleotide 28-mer homopolymer of cytidine (SdC28) inhibited the phosphatidylserine and Ca2+-dependent phosphorylation of an epidermal growth factor receptor octapeptide substrate. The inhibition by suramin was mixed competitive/noncompetitive with respect to ATP, but uncompetitive with respect to substrate. In contrast, the inhibition by SdC28 was competitive with respect to substrate (Ki = 5.4 microM) and not competitive with respect to ATP. The PKC alpha and beta1 isoforms were inhibited to the same extent with SdC28, while PKC epsilon was not inhibited. SdC28, in the absence of lipid cofactor, stimulated substrate phosphorylation, and in the absence of substrate induced PKC beta1 autophosphorylation. Similar behavior was seen with another polyanion, the polysulfated carbohydrate pentosan polysulfate (polyxylyl hydrogen sulfate). H4, a bis-naphthalene disulfonate tetraanion structurally related to suramin, also inhibited kinase activity but was not competitive with respect to ATP. Dianions closely related to H4 failed to inhibit PKC beta1, suggesting that multiple (>2) negative charges are required. The interactions of polyanions with PKC are complex, and are dependent on the molecular structure of the polyanion, the presence of cofactors, and the PKC isoform.
Khaled
Z
Z
Department of Medicine, Columbia University, New York, New York 10032, USA.
Rideout
D
D
O'Driscoll
K R
KR
Petrylak
D
D
Cacace
A
A
Patel
R
R
Chiang
L C
LC
Rotenberg
S
S
Stein
C A
CA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007700:Kinetics; D051379:Mice; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D010426:Pentosan Sulfuric Polyester / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D013498:Suramin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013873:Thionucleotides
D000970:Antineoplastic Agents; D007527:Isoenzymes; D009838:Oligodeoxyribonucleotides; D011994:Recombinant Proteins; D013873:Thionucleotides; D010426:Pentosan Sulfuric Polyester; D013498:Suramin; C497259:Prkcd protein, mouse; C496630:Prkca protein, mouse; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta