The antiproliferative effects of staurosporine are not exclusively mediated by inhibition of protein kinase C.
The effects of the kinase inhibitor staurosporine on mitogenesis in NIH/3T3 fibroblasts were characterized. In the presence of serum, staurosporine caused dose- and time-dependent inhibitions of [3H]thymidine incorporation into DNA (IC50 approximately 0.1 nM after 24 hr). Depletion of protein kinase C (PKC) by treatment of the cells with phorbol myristate acetate (PMA) for 24 hr did not affect the rate of DNA synthesis either in the absence or presence of staurosporine. Down-regulation of PKC did not affect the basal rate of [3H]thymidine incorporation in serum-starved cells, or mitogenesis in response to serum or epidermal growth factor (EGF). Proliferation in response to PMA, platelet derived growth factor (PDGF), insulin and fibroblast growth factor (FGF) was inhibited by PKC-depletion. Dose response curves for staurosporine-mediated inhibition of DNA synthesis were essentially parallel for insulin, EGF, FGF, PDGF and PMA; however, mitogenesis in response to serum was more resistant to staurosporine. Therefore, staurosporine appears to be equally effective in inhibiting mitogenesis induced by activation of PKC and by activation of receptor tyrosine kinases.
Smith
C D
CD
Division of Cell Biology, Burroughs Wellcome Co., Research Triangle Park, NC 27709.
Glickman
J F
JF
Chang
K J
KJ
D000470:Alkaloids / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D019311:Staurosporine; D013936:Thymidine / Q000378:metabolism
D000470:Alkaloids; D004247:DNA; D011493:Protein Kinase C; D019311:Staurosporine; D013936:Thymidine