Inhibition of cellular growth and induction of apoptosis in pituitary adenoma cell lines by the protein kinase C inhibitor hypericin: potential therapeutic application

1996 ◽  
Vol 85 (2) ◽  
pp. 329-334 ◽  
Author(s):  
H. Bruce Hamilton ◽  
David R. Hinton ◽  
Ronald E. Law ◽  
Rayudu Gopalakrishna ◽  
Yu Zhuang Su ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Pituitary Adenoma ◽  
Protein Kinase ◽  
Tumor Cells ◽  
Cell Lines ◽  
Cellular Growth ◽  
Pituitary Cells ◽  
Adenoma Cell ◽  
Kinase C ◽  
Normal Human

✓ Protein kinase C (PKC) is an enzyme involved in the regulation of cellular growth, proliferation, and differentiation in a number of tissues including the anterior pituitary, in which it is also believed to play a role in hormone secretion. Protein kinase C activity and expression have been found to be greater in adenomatous pituitary cells than in normal human and rat pituitary cells and higher in invasive pituitary tumor cells than in noninvasive ones. Inhibition of PKC activity has been shown in a variety of tumor cells to inhibit growth in a dose-related fashion. The purpose of the current study was to determine whether hypericin, a potent inhibitor of PKC activity that may be administered clinically, alters the growth and proliferation in established pituitary adenoma lines and to determine if inhibition of PKC activity induces apoptosis, as reported in some other tumor cell types. Two established pituitary adenoma cell lines, AtT-20 and GH4C1, were treated with hypericin in tissue culture for defined periods following passage. Inhibition of growth was found to be dose dependent in all three cell lines in low micromolar concentrations of hypericin, as determined by viable cell counts, methylthiotetrazole assay, and [3H]thymidine uptake studies. Concentrations of hypericin as low as 100 nM also induced apoptosis in these established lines, whereas treatment of normal human fibroblasts with a concentration of 10 µM failed to induce apoptosis. The potential use of hypericin in the therapy of pituitary adenomas warrants additional in vitro investigations with the aim of later moving toward therapeutic trials in selected patients in whom surgical or medical therapy has failed.

The identification of four protein kinase C isoforms in human glioblastoma cell lines: PKC alpha, gamma, epsilon, and zeta

1994 ◽  
Vol 81 (5) ◽  
pp. 734-740 ◽  
Author(s):  
Haiguang Xiao ◽  
David A. Goldthwait ◽  
Timothy Mapstone
Keyword(s):  
Plasma Membrane ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Cell Lines ◽  
Glioblastoma Cell ◽  
Kinase C ◽  
Normal Human ◽  
Pkc Ζ ◽  
Glial Cell Cultures ◽  
Glioblastoma Cell Lines

✓ Levels of protein kinase C (PKC) isoforms in eight human glioblastoma cell lines and two normal human glial cell cultures were determined. Earlier studies identified PKC-α and PKC-γ in these cell lines but PKC-β was not present. In this study, PKC-ϵ and PKC-ζ are demonstrated immunologically in these cell lines and also in two normal human glial cell cultures. Protein kinase C-δ was not present. When levels of the four isoforms in the tumor cells were compared to levels in the normal cells, no increase was observed in PKC-α or PKC-γ, but PKC-ϵ was elevated three to 30 times in six of the eight tumors, and PKC-ζ was elevated approximately two times in all of the tumors. Incubation of cell line A172 with phorbol ester for 6 hours resulted in a 48-fold maximum increase in the nuclear PKC-ϵ and a sevenfold increase in the plasma membrane fraction with no change in the cytoplasmic fraction. A similar incubation for 4 hours produced a 0.5- to onefold increase of PKC-ζ in cytoplasmic, nuclear, and plasma membrane fractions. Other researchers have shown that overexpression of PKC-ϵ in fibroblasts results in tumorigenesis, and that blocking PKC-ζ function inhibits deoxyribonucleic acid synthesis. These data suggest that alteration in the expression of PKC-ϵ and PKC-ζ could be a factor in the conversion of normal glial cells to glioblastomas.

scholarly journals Protein kinase C mediates mutant N-Ras–induced developmental abnormalities in normal human erythroid cells

Blood ◽  
2002 ◽  
Vol 100 (12) ◽  
pp. 4185-4192 ◽  
Author(s):  
Richard L. Darley ◽  
Lorna Pearn ◽  
Nader Omidvar ◽  
Marion Sweeney ◽  
Janet Fisher ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Myeloid Leukemia ◽  
Colony Growth ◽  
Developmental Abnormalities ◽  
Ras Mutations ◽  
Molecular Abnormalities ◽  
Kinase C ◽  
Poor Understanding ◽  
Normal Human

RAS mutations are one of the most frequent molecular abnormalities associated with myeloid leukemia and preleukemia, yet there is a poor understanding of how they contribute to the pathogenesis of these conditions. Here, we describe the consequences of ectopic mutant N-Ras (N-Ras*) expression on normal human erythropoiesis. We show that during early (erythropoietin [EPO]–independent) erythropoiesis, N-Ras* promoted the amplification of a phenotypically primitive but functionally defective subpopulation of CD34+ erythroblasts. N-Ras* also up-regulated the expression of megakaryocyte antigens on human erythroblasts. Although early erythroblasts expressing N-Ras* were able to respond to erythropoietin and generate mature progeny, this occurred with greatly reduced efficiency, probably explaining the poor colony growth characteristics of these cells. We further report that this oncogene promoted the expression and activation of protein kinase C (PKC) and that the effects of N-Ras* on erythropoiesis could be abrogated or attenuated by inhibition of PKC. Similarly, the effects of this oncogene could be partially mimicked by treatment with PKC agonist. Together, these data suggest that expression of N-Ras* is able to subvert the normal developmental cues that regulate erythropoiesis by activating PKC. This gives rise to phenotypic and functional abnormalities commonly observed in preleukemia, suggesting a direct link between RAS mutations and the pathogenesis of preleukemia.

scholarly journals Nanog expression is negatively regulated by protein kinase C activities in human cancer cell lines

2013 ◽  
Vol 34 (7) ◽  
pp. 1497-1509 ◽  
Author(s):  
Wing-Keung Chu ◽  
Pei-Min Dai ◽  
Hsin-Lun Li ◽  
Chia-Chu Pao ◽  
Jan-Kan Chen
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines ◽  
Nanog Expression ◽  
Kinase C

scholarly journals Differential responsiveness of intestinal epithelial cells to 1,25-dihydroxyvitamin D3--role of protein kinase C

2001 ◽  
Vol 169 (1) ◽  
pp. 145-151 ◽  
Author(s):  
HJ Armbrecht ◽  
MA Boltz ◽  
TL Hodam ◽  
VB Kumar
Keyword(s):  
Vitamin D ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Cell Lines ◽  
Phorbol Esters ◽  
Mrna Levels ◽  
Intestinal Epithelial ◽  
Vitamin D Receptors ◽  
Kinase C ◽  
Crypt Cells

Non-transformed rat intestinal epithelial cell (IEC) lines were used to study the action of 1,25-dihydroxyvitamin D(3) (1,25(OH)2D) in the intestine. The capacity of 1,25(OH)2D to increase the expression of the cytochrome P450 component of the vitamin D 24-hydroxylase (CYP24) was determined in IEC-6 and IEC-18 cell lines. In IEC-6 cells, which are derived from crypt cells isolated from the whole small intestine, 1,25(OH)2D markedly increased expression of CYP24 protein and mRNA within 12 h. In contrast, in IEC-18 cells, which are derived from crypt cells from the ileum only, 1,25(OH)2D did not increase expression of CYP24 until 24-48 h. The maximal levels of CYP24 mRNA seen in the IEC-18 cells were only 31% of the maximal levels seen in the IEC-6 cells. In the presence of 1,25(OH)2D, phorbol esters rapidly increased CYP24 mRNA levels in IEC-18 cells from almost undetectable to levels seen in IEC-6 cells. Protein kinase inhibitors abolished the stimulation by 1,25(OH)2D and by phorbol esters in both cell lines. Stimulation of mRNA levels by phorbol esters required new protein synthesis but stimulation by 1,25(OH)2D did not. These studies demonstrated that the rapid action of 1,25(OH)2D in IEC-6 cells is related to the activation of protein kinase C, an event which is missing in the IEC-18 cells. This differential response to 1,25(OH)2D probably takes place at a post-receptor site, since the number of vitamin D receptors in each cell line was found to be similar.

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