Okadaic acid inhibits PDGF-induced proliferation and decreases PDGF receptor number in C3H/10T1/2 mouse fibroblasts.
Okadaic acid is both a potent inhibitor of protein serine/threonine phosphatases and a tumor promoter in the mouse skin model. We have previously shown that at non-toxic nanomolar concentrations okadaic acid reversibly inhibits induction (promotion) by PDGF of transformed cells by the 'complete' and 'two-stage' protocols in the C3H/10T1/2 mouse fibroblast transformation assay. In the present study we have demonstrated that treatment of confluent and proliferatively quiescent C3H/10T1/2 mouse fibroblasts with low doses of okadaic acid inhibits the platelet-derived growth factor (PDGF)-induced mitogenic response. This inhibition is accompanied by a loss of PDGF binding sites, a decreased PDGF-induced phosphatidylinositol turnover and a decrease in the PDGF-induced intracellular calcium signal. The decrease in the PDGF-generated intracellular signalling processes represents a mechanism by which okadaic acid inhibits PDGF-induced proliferation and the promotion of in vitro neoplastic transformation by PDGF.
Dean
N M
NM
Cancer Research Center of Hawaii, University of Hawaii, Honolulu 96813.
Mordan
L J
LJ
Tse
K
K
Mooberry
S L
SL
Boynton
A L
AL
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D004815:Epidermal Growth Factor / Q000378:metabolism; D004988:Ethers, Cyclic / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000648:ultrastructure; D007295:Inositol Phosphates / Q000378:metabolism; D007424:Intracellular Fluid / Q000378:metabolism; D007457:Iodine Radioisotopes; D051379:Mice; D019319:Okadaic Acid; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000187:drug effects* / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D004988:Ethers, Cyclic; D007295:Inositol Phosphates; D007457:Iodine Radioisotopes; D010982:Platelet-Derived Growth Factor; D011956:Receptors, Cell Surface; D014662:Vasoconstrictor Agents; D019319:Okadaic Acid; D004815:Epidermal Growth Factor; D004247:DNA; D017479:Receptors, Platelet-Derived Growth Factor; D002118:Calcium