scholarly journals Protein kinase C activators suppress stimulation of capillary endothelial cell growth by angiogenic endothelial mitogens.

1987 ◽  
Vol 104 (3) ◽  
pp. 679-687 ◽  
Author(s):  
S R Doctrow ◽  
J Folkman
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cells ◽  
Protein Kinase C ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Protein Kinase ◽  
Cell Growth ◽  
Human Hepatoma ◽  
Kinase C ◽  
Protein Kinase C Activators

The intracellular events regulating endothelial cell proliferation and organization into formalized capillaries are not known. We report that the protein kinase C activator beta-phorbol 12,13-dibutyrate (PDBu) suppresses bovine capillary endothelial (BCE) cell proliferation (K50 = 6 +/- 4 nM) and DNA synthesis in response to human hepatoma-derived growth factor, an angiogenic endothelial mitogen. In contrast, PDBu has no effect on the proliferation of bovine aortic endothelial cells and is mitogenic for bovine aortic smooth muscle and BALB/c 3T3 cells. Several observations indicate that the inhibition of human hepatoma-derived growth factor-stimulated BCE cell growth by PDBu is mediated through protein kinase C. Different phorbol compounds inhibit BCE cell growth according to their potencies as protein kinase C activators (12-O-tetradecanoylphorbol 13-acetate greater than PDBu much greater than beta-phorbol 12,13-diacetate much much greater than beta-phorbol; alpha-phorbol 12,13-dibutyrate; alpha-phorbol 12,13-didecanoate). PDBu binds to a single class of specific, saturable sites on the BCE cell with an apparent Kd of 8 nM, in agreement with reported affinities of PDBu for protein kinase C in other systems. Specific binding of PDBu to BCE cells is displaced by sn-1,2-dioctanoylglycerol, a protein kinase C activator and an analog of the putative second messenger activating this kinase in vivo. The weak protein kinase C activator, sn-1,2-dibutyrylglycerol, does not affect PDBu binding. A cytosolic extract from BCE cells contains a calcium/phosphatidylserine-dependent protein kinase that is activated by sn-1,2-dioctanoylglycerol and PDBu, but not by beta-phorbol. These findings indicate that protein kinase C activation can cause capillary endothelial cells to become desensitized to angiogenic endothelial mitogens. This intracellular regulatory mechanism might be invoked during certain phases of angiogenesis, for example when proliferating endothelial cells become differentiated to organize into nongrowing tubes.

scholarly journals Fibroblast Growth Factor-2 Autofeedback Regulation in Pituitary Folliculostellate TtT/GF Cells

Endocrinology ◽  
2009 ◽  
Vol 150 (7) ◽  
pp. 3252-3258 ◽  
Author(s):  
George Vlotides ◽  
Yen-Hao Chen ◽  
Tamar Eigler ◽  
Song-Guang Ren ◽  
Shlomo Melmed
Keyword(s):  
Cell Proliferation ◽  
Protein Kinase C ◽  
Growth Factor ◽  
Protein Kinase ◽  
Cell Growth ◽  
Fibroblast Growth Factor ◽  
Focal Adhesion ◽  
Fibroblast Growth ◽  
Src Tyrosine Kinase ◽  
Kinase C

To investigate paracrine regulation of pituitary cell growth, we tested fibroblast growth factor (FGF) regulation of TtT/GF folliculostellate (FS) cells. FGF-2, and FGF-4 markedly induced cell proliferation, evidenced by induction of pituitary tumor transforming gene-1 (Pttg1) mRNA expression and percentage of cells in S phase. Signaling for FGF-2-induced FS cell proliferation was explored by specific pharmacological inhibition. A potent inhibitory effect on FGF-2 action was observed by blocking of Src tyrosine kinase with 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d] pyrimidine (≥0.1 μm), followed by protein kinase C (PKC) inhibition with GF109203X. Treatment with FGF-2 (30 ng/ml; 10 min) activated phosphorylation of signal transducer and activator of transcription-3, ERK, stress-activated protein kinase/c-Jun N-terminal kinase, Akt, and focal adhesion kinase. Src inhibition with 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d] pyrimidine suppressed FGF-2-induced Akt and focal adhesion kinase, indicating effects downstream of FGF-2-induced Src activation. FGF-2 also markedly induced its own mRNA expression, peaking at 2–4 h, and this effect was suppressed by Src tyrosine kinase inhibition. The PKC inhibitor GF109203X abolished FGF-2 autoinduction, indicating PKC as the primary pathway involved in FGF-2 autoregulation in these cells. In addition to pituitary FGF-2 paracrine activity on hormonally active cells, these results show an autofeedback mechanism for FGF-2 in non-hormone-secreting pituitary FS cells, inducing cell growth and its own gene expression, and mediated by Src/PKC signaling.

scholarly journals Potentiation response of cultured human uterine leiomyoma cells to various growth factors by endothelin-1: role of protein kinase C

2001 ◽  
pp. 543-548 ◽  
Author(s):  
I Eude ◽  
E Dallot ◽  
MC Vacher-Lavenu ◽  
C Chapron ◽  
F Ferre ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Protein Kinase C ◽  
Growth Factors ◽  
Growth Factor ◽  
Protein Kinase ◽  
Cell Growth ◽  
Endothelin 1 ◽  
Kinase C ◽  
Pkc Isoforms

OBJECTIVE: Factors responsible for the abnormal proliferation of myometrial cells that accompanies leiomyoma formation are unknown, although steroid hormones and peptide growth factors have been implicated. We hypothesized that endothelin-1 (ET-1) is a physiological regulator of tumor growth. DESIGN: In this study, we investigated the role of ET-1 on growth of human leiomyoma cells and its synergistic effect with growth factors, as well as the signaling pathway involved in this interaction. METHODS: Leiomyoma cell proliferation was assayed by [H]thymidine incorporation and cell number. Protein kinase C (PKC) isoforms were analyzed by Western blot using specific antibodies. RESULTS: ET-1 on its own was unable to stimulate DNA synthesis but potentiated the leiomyoma cell growth effects of basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), IGF-I and IGF-II. The failure of a protein tyrosine kinase (PTK) inhibitor, tyrphostin 51, to affect the potentiating effect of ET-1, supports the hypothesis of non-involvement of PTK in this process. The inhibition of PKC by calphostin C or its down-regulation by phorbol 12,13-dibutyrate (PDB) eliminated the potentiating effect of ET-1, but did not block cell proliferation induced by the growth factors alone. Five PKC isoforms (alpha, beta1, epsilon, delta and zeta) were detected in leiomyoma cells, but only phorbol ester-sensitive PKC isoforms (PKCalpha, epsilon and delta) contribute to the potentiating effect of leiomyoma cell growth by ET-1. CONCLUSIONS: We have demonstrated that ET-1 potentiates leiomyoma cell proliferation to growth factors through a PKC-dependent pathway. These findings suggest a possible involvement of ET-1 in the pathogenesis of leiomyomas.

scholarly journals Induction of heparin-binding epidermal growth factor-like growth factor mRNA by protein kinase C activators

1994 ◽  
Vol 46 (3) ◽  
pp. 690-695 ◽  
Author(s):  
Mian-Shin Tan ◽  
Jer-Chia Tsai ◽  
Yau-Jiunn Lee ◽  
Hung-Chun Chen ◽  
Shyi-Jang Shin ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Growth Factor ◽  
Protein Kinase ◽  
Epidermal Growth Factor ◽  
Heparin Binding ◽  
Kinase C ◽  
Protein Kinase C Activators ◽  
Epidermal Growth

scholarly journals Basic fibroblast growth factor requires a long-lasting activation of protein kinase C to induce cell proliferation in transformed fetal bovine aortic endothelial cells.

1991 ◽  
Vol 2 (9) ◽  
pp. 719-726 ◽  
Author(s):  
M Presta ◽  
L Tiberio ◽  
M Rusnati ◽  
P Dell'Era ◽  
G Ragnotti
Keyword(s):  
Cell Proliferation ◽  
Protein Kinase C ◽  
Growth Factor ◽  
Protein Kinase ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth ◽  
Mitogenic Response ◽  
Kinase C ◽  
Fetal Bovine ◽  
Induce Cell Proliferation

Basic fibroblast growth factor (bFGF) induces a protein kinase C (PKC)-dependent mitogenic response in transformed fetal bovine aortic endothelial GM 7373 cells. A long-lasting interaction of bFGF with the cell is required to induce cell proliferation. bFGF-treated cells are in fact committed to proliferate only after they have entered the phase S of the cell cycle, 12-14 h after the beginning of bFGF treatment. Before that time, the mitogenic response to bFGF is abolished by 1) removal of extracellular bFGF by suramin, 2) addition of neutralizing anti-bFGF antibodies to the culture medium, 3) inhibition of PKC activity by the protein kinase inhibitor H-7, and 4) down-regulation of PKC by cotreatment with phorbol ester. Thus the requirement for a prolonged interaction of bFGF with the cell reflects the requirement for a prolonged activation of PKC. Similar conclusions can be drawn for the PKC activators 12-O-tetradecanoyl phorbol 13-acetate and 1,2-dioctanoyl-sn-glycerol. The two molecules require 16 and 6 h, respectively, of activation of PKC to induce 50% of maximal cell proliferation. The requirement for a long-lasting activation of PKC appears to be a mechanism for the control of cell proliferation capable of discriminating among transient nonmitogenic stimuli and long-lasting mitogenic stimuli.

The PKC- Inhibitor Enzastaurin Inhibits MM Cell Growth, Survival and Migration in the Bone Marrow Microenvironment.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1584-1584 ◽  
Author(s):  
Klaus Podar ◽  
Marc S. Raab ◽  
Dean Abtahi ◽  
Yu-Tzu Tai ◽  
Boris Lin ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Protein Kinase C ◽  
Cell Migration ◽  
Protein Kinase ◽  
Cell Growth ◽  
Cell Lines ◽  
Pkc Inhibitor ◽  
Kinase C ◽  
Pkc Signaling ◽  
And Migration

Abstract Members of the protein kinase C (PKC) family of serine- threonine protein kinases mediate multiple physiological functions including differentiation, growth and survival, invasiveness, angiogenesis and drug efflux. Dysregulation of PKC signaling has been implicated in tumor progression and prompted the development of novel anticancer therapeutics. In multiple myeloma (MM) PKC isoforms are: (1) involved in MM cell apoptosis; (2) associated with VEGF- and Wnt- induced MM cell migration; and (3) controlling shedding of IL-6 receptor alpha. However, to date the potential of targeting PKC signaling sequelae in MM has not been evaluated. Here we investigated the novel orally available protein- kinase C (PKC) inhibitor Enzastaurin (Eli Lilly and Company) for its therapeutic efficacy in MM. We first tested the ability of Enzastaurin to suppress MM cell proliferation in a wide array of MM cell lines. Our data show that Enzastaurin inhibits 3H[dT] uptake in all cell lines tested in a low micromolar range equivalent to the concentration range achieved in the patient plasma during clinical trials. Importantly, Enzastaurin also abrogates MM cell proliferation in a BMSC-MM coculture system. We next sought to determine whether Enzastaurin can inhibit cell survival and found dose- dependent induction of MM cell apoptosis in MM cell lines MM.1S, MM.1R, OPM-1, OPM-2, RPMI-8226, and RPMI-dox40. Moreover, Enzastaurin significantly inhibited VEGF- induced MM cell migration on fibronectin. Importantly, IGF-1- induced MM cell migration was abrogated by Enzastaurin, demonstrating the requirement of PKC. Signaling pathways mediating these effects were next examined: Our data show that Enzastaurin abrogates phosphorylation of Akt and GSK3beta, which is required for MM cell growth and migration. Furthermore, ongoing studies are evaluating the efficacy of Enzastaurin in a murine model of human MM. Taken together, these studies show for the first time the preclinical efficacy of the orally available PKC inhibitor Enzastaurin providing the basis for its clinical evaluation to improve patient outcome in MM.

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