Synthesis of diacylglycerol de novo is responsible for permanent activation and down-regulation of protein kinase C in transformed cells

Chiarugi, Vincenzo; Bruni, Paola; Pasquali, Franca; Magnelli, Lucia; Basi, Gabriele; Ruggiero, Marco; Farnararo, Marta

doi:10.1016/0006-291x(89)91532-5

Cited by 37 publications

(14 citation statements)

References 26 publications

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“…Therefore, the increased PA and DAG mass in ras-transformed cells results from phospholipid turnover (see Introduction). An increased turnover of newly synthesized PC may explain why the labeling of DAG with [ 14 C]glucose is increased after incubating ras-transformed ®broblasts for 30 min (Chiarugi et al, 1989). In our experiments, the ratio of 14 C in PA relative to DAG was increased in transformed ®broblasts.…”

Section: Discussionsupporting

confidence: 49%

“…Increased signaling by DAG in ras-transformed cells could arise from increased DAG synthesis de novo (Chiarugi et al, 1989), or increased phospholipid turnover. The latter possibility is supported by the observation that injection of NIH3T3 ®broblasts with antibodies that neutralize PLC-g blocks DNA synthesis induced by co-injected p21 ras (Smith et al, 1990).…”

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confidence: 99%

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Increased concentrations of phosphatidate, diacylglycerol and ceramide in ras- and tyrosine kinase (fps)-transformed fibroblasts

et al. 1997

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Concentrations of the bioactive lipids, phosphatidate and diacylglycerol, increased with time in culture in ras-and tyrosine kinase (fps)-transformed ®broblasts but not in control ®broblasts. On Day 3, diacylglycerol and phosphatidate concentrations were about 3.3-and 5.5-fold higher respectively in the ras-transformed compared to control ®broblasts. These concentrations in fpstransformed ®broblasts were increased about twofold. The changes in phosphatidate and diacylglycerol resulted from enhanced phospholipid turnover rather than from synthesis de novo. The increased ratio of phosphatidate to diacylglycerol is explained by decreased activities of two distinct phosphatidate phosphohydrolases and increased diacylglycerol kinase in ras-transformed ®bro-blasts. Ceramide concentrations were about 2.5-and threefold higher in the fps-and ras-transformed cells respectively on Day 3 compared to the controls. Incubating control ®broblasts from Days 1 to 3 with phosphatidylcholine-speci®c phospholipase C increased diacylglycerol, phosphatidate and ceramide concentrations, and decreased Mg 2+ -independent-phosphatidate phosphohydrolase activity. 8-(4-chlorophenylthio)-cAMP had a cytostatic e ect in ras-transformed cells, it decreased the concentrations of phosphatidate and diacylglycerol, but increased that of ceramide. The consequences of increased ceramide and phosphatidate concentrations in ras-transformed cells are discussed in relation to signal transduction, cell division and the transformed phenotype.

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Section: Discussionsupporting

confidence: 49%

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confidence: 99%

Increased concentrations of phosphatidate, diacylglycerol and ceramide in ras- and tyrosine kinase (fps)-transformed fibroblasts

et al. 1997

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“…Levels of diacylglycerol (DAGs), which activate PKC, seem to be increased in transformed cells (Preiss et al, 1986;Weyman et al, 1988). An elevated DAG content of malignant cells may derive from a constitutively enhanced DAG de novo synthesis, and may cause long-lasting activation and downregulation of PKC (Chiarugi et al, 1989). Spread of malignant tumour cells within the host organism can be modulated by agents stimulating PKC.…”

Section: Discussionmentioning

confidence: 99%

Effects of staurosporine, K 252a and other structurally related protein kinase inhibitors on shape and locomotion of Walker carcinosarcoma cells

Zimmermann

Keller²

1992

Br J Cancer

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Summary The structure/activity relationship of the protein kinase inhibitors, staurosporine and K 252a and their analogues on motility of Walker carcinosarcoma cells has been studied in vitro. Staurosporine and K 252a, similar to phorbol myristate acetate (PMA) and diacylglycerols, suppress cell polarity and locomotor activity of Walker carcinosarcoma cells. Staurosporine inhibits spontaneous and colchicine-induced front-tail polarity (IDm of about 6.0 x 10-8 M) as well as spontaneous and colchicine-stimulated locomotion at 10-7 M. K 252a suppresses cell polarity (IDm of about 4.5 x 10-6 M) and inhibits spontaneous and colchicinestimulated locomotion at I0-I M, but suppression of locomotor activity is not complete in the presence of colchicine. CGP 41251, a staurosporine derivative with a much higher specificity for protein kinase C (PKC) than staurosporine, induces a dose-dependent increase in the proportion of polarised cells, and stimulates cell locomotion. Two K 252a analogues, KT 5720 and KT 5822, which act preferentially on cyclic nucleotidedependent protein kinases, and CGP 42700, an inactive staurosporine analogue, had no effect on cell polarity and locomotion. The findings suggest that protein kinase inhibitors acting preferentially on PKC may be of interest in pharmacological regulation of tumour cell locomotion.

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“…These data indicate that PKC β II plays a direct role in the development of colon cancer. Recently it has become apparent that oncogenic transformation of the colon is associated with an initial time-dependent accumulation of intracellular diacylglycerol (DAG) (43)(44)(45), which may be responsible for the observed down-regulation of colonic PKC α, δ and ζ expression and activity (8,(46)(47)(48). The exception to this response is PKC β II , which is not down-regulated efficiently in colonocytes following exposure to PKC activators (13,14).…”

Section: Discussionmentioning

confidence: 99%

Morphodensitometric analysis of protein kinase C βII expression in rat colon: modulation by diet and relation to in situ cell proliferation and apoptosis

et al. 2000

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We have recently demonstrated that overexpression of PKC β II renders transgenic mice more susceptible to carcinogeninduced colonic hyperproliferation and aberrant crypt foci formation. In order to further investigate the ability of PKC β II to modulate colonocyte cytokinetics, we determined the localization of PKC β II with respect to cell proliferation and apoptosis along the entire colonic crypt axis following carcinogen and diet manipulation. Rats were provided diets containing either corn oil [containing n-6 polyunsaturated fatty acids (PUFA)] or fish oil (containing n-3 PUFA), cellulose (non-fermentable fiber) or pectin (fermentable fiber) and injected with azoxymethane (AOM) or saline. After 16 weeks, an intermediate time point when no macroscopic tumors are detected, colonic sections were utilized for immunohistochemical image analysis and immunoblotting. Cell proliferation was measured by incorporation of bromodeoxyuridine into DNA and apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling. In the distal colon, PKC β II staining was localized to the upper portion of the crypt. In comparison, proximal crypts had more (P < 0.05) staining in the lower tertile. AOM enhanced (P < 0.05) PKC β II expression in all regions of the distal colonic crypt (upper, middle and lower tertiles). There was also an interaction (P < 0.05) between dietary fat and fiber on PKC β II expression (corn/pectin > fish/cellulose, fish/pectin > corn/cellulose) in all regions of the distal colonic crypt. With respect to colonic cell kinetics, proliferation paralleled the increase in PKC β II expression in carcinogen-treated animals. In contrast, apoptosis at the lumenal surface was inversely proportional to PKC β II expression in the upper tertile. These results suggest that an elevation in PKC β II expression along the crypt axis in the distal colon is linked to enhancement of cell proliferation and suppression of apoptosis, predictive intermediate biomarkers of tumor development. Therefore, select dietary factors may confer protection against colon carcinogenesis in part by blocking carcinogen-induced PKC β II expression.Abbreviations: AOM, azoxymethane; BrdU, bromodeoxyuridine; BT, biotinyl tyramide/amplification diluent; DAG, diacylglycerol; PBS, phosphate-buffered saline; PKC, protein kinase C; PUFA, polyunsaturated fatty acids; SA-HRP, streptavidin-conjugated horseradish peroxidase.

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Synthesis of diacylglycerol de novo is responsible for permanent activation and down-regulation of protein kinase C in transformed cells

Cited by 37 publications

References 26 publications

Increased concentrations of phosphatidate, diacylglycerol and ceramide in ras- and tyrosine kinase (fps)-transformed fibroblasts

Increased concentrations of phosphatidate, diacylglycerol and ceramide in ras- and tyrosine kinase (fps)-transformed fibroblasts

Effects of staurosporine, K 252a and other structurally related protein kinase inhibitors on shape and locomotion of Walker carcinosarcoma cells

Morphodensitometric analysis of protein kinase C βII expression in rat colon: modulation by diet and relation to in situ cell proliferation and apoptosis

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