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195 Insulin and cell growth: studies in normal and transformed endothelial cells
65s
193
IS THE
SECOND
MESSENGER
CAMP
ANTAGONIST
INVOLVED
IN CANCER
?
H.K. Wasner, Diabetes-Forschungsinstitut Auf'm Hennekamp 65, 4000 Dusseldorf, FRG chemically identified as The intracellular regulator CAMP antagonist, prostaglandyl-inositol cyclic phosphate, signals relaxation, terminaIt acts by inhibiting CAMP-dependent tion of energy consumption... protein kinase and by activating phosphoprotein phosphatase (H.K. Wasner (1975) FEBS lett.57, 60 - 63; (1981)FEBS lett.133, 260 - 264). released from cells, but unlike CAMP 1. Like CAMP it is metabolically it reenters cells. When intact cells are exposed to CAMP antagonist, regulatory effects opposite to those expected are observed. are dramatically in2. In many types of cancer prostaglandin-levels creased with a concomitant enhancement of CAMP antagonist synthesis. These findings suggest that in cancer extracellularly elevated CAMPantagonist levels lead to opposite intracellular regulatory effects in surrounding tissues. By this way the normal effect of CAMP antagonist upon cellular recovery and energy restoration is counteracted leading to cachexia.
194
CYCLIC AMP INHIBITS THE GROWTH OF HUMAN BREAST CANCER MEDIUM. Ian S. Fentiman and Joyce Taylor-Papadimitriou Imperial Cancer Research Fund, London, England, U.K.
CELLS
IN DEFINED
Well
characterized human breast cancer cells have been grown in chemiThis cell proliferation can be incally defined medium without serum. adenyl cyclase activators and phosphohibited by cyclic AMP analogues, diesterase inhibitors. This contrasts with normal human mammary cells whose growth is stimulated by agents which elevate intracellular cyclic AMP.
195
INSULIN AND CELL GROWTH: STUDIES IN NORMAL AND TRANSFORMED ENDOTHELIAL CELLS N. Kaiser, I. Vlodavsky*, A. Tur-Sinai, Z. Fuks* and E. Cerasi, Dept. of Endocrinology and Metabolism, and Dept. of Oncology*, Hebrew University-Hadassah Medical Center, Jerusalem, Israel. Vascular endothelial cell cultures were used to study the modulation of insulin receptor binding and processing, and its mitogenic action by cell growth and differentiation. Three types of cultures were investigated: (1) confluent, contact inhibited monolayer cultures resembling the in viva tissue; (2) subconfluent, not yet organized monolayer cultures, representing proliferating endothelium; and (3) endothelial cells modified to lose the property of contact inhibition, growing in multiple layers. All three cultures exhibited specific binding of l2fiI-insulin and were capable of degrading it. Insulin binding per cell was 2.4 and 10 fold higher in the subconfluent and modified cultures, respectively, as compared to the confluent cultures. Similarly, the rate of insulin degradation was higher in the subconfluent and nwdified cultures (2.3 and 20 fold, respectively). The increase in insulin binding and processing under conditions of cell growth suggests a role for insulin in the regulation of endothelial cell proliferation. However, insulin was found to stimulate DNA synthesis only in sparse, serum starved normal endothelial cells and not in the variant cells which lost the property of contact inhibition. This may imply a differential role for insulin in the regulation of growth in normal and transformed endothelial cells, which may result from a post-receptor defect in the variant cells.
193
IS THE
SECOND
MESSENGER
CAMP
ANTAGONIST
INVOLVED
IN CANCER
?
H.K. Wasner, Diabetes-Forschungsinstitut Auf'm Hennekamp 65, 4000 Dusseldorf, FRG chemically identified as The intracellular regulator CAMP antagonist, prostaglandyl-inositol cyclic phosphate, signals relaxation, terminaIt acts by inhibiting CAMP-dependent tion of energy consumption... protein kinase and by activating phosphoprotein phosphatase (H.K. Wasner (1975) FEBS lett.57, 60 - 63; (1981)FEBS lett.133, 260 - 264). released from cells, but unlike CAMP 1. Like CAMP it is metabolically it reenters cells. When intact cells are exposed to CAMP antagonist, regulatory effects opposite to those expected are observed. are dramatically in2. In many types of cancer prostaglandin-levels creased with a concomitant enhancement of CAMP antagonist synthesis. These findings suggest that in cancer extracellularly elevated CAMPantagonist levels lead to opposite intracellular regulatory effects in surrounding tissues. By this way the normal effect of CAMP antagonist upon cellular recovery and energy restoration is counteracted leading to cachexia.
194
CYCLIC AMP INHIBITS THE GROWTH OF HUMAN BREAST CANCER MEDIUM. Ian S. Fentiman and Joyce Taylor-Papadimitriou Imperial Cancer Research Fund, London, England, U.K.
CELLS
IN DEFINED
Well
characterized human breast cancer cells have been grown in chemiThis cell proliferation can be incally defined medium without serum. adenyl cyclase activators and phosphohibited by cyclic AMP analogues, diesterase inhibitors. This contrasts with normal human mammary cells whose growth is stimulated by agents which elevate intracellular cyclic AMP.
195
INSULIN AND CELL GROWTH: STUDIES IN NORMAL AND TRANSFORMED ENDOTHELIAL CELLS N. Kaiser, I. Vlodavsky*, A. Tur-Sinai, Z. Fuks* and E. Cerasi, Dept. of Endocrinology and Metabolism, and Dept. of Oncology*, Hebrew University-Hadassah Medical Center, Jerusalem, Israel. Vascular endothelial cell cultures were used to study the modulation of insulin receptor binding and processing, and its mitogenic action by cell growth and differentiation. Three types of cultures were investigated: (1) confluent, contact inhibited monolayer cultures resembling the in viva tissue; (2) subconfluent, not yet organized monolayer cultures, representing proliferating endothelium; and (3) endothelial cells modified to lose the property of contact inhibition, growing in multiple layers. All three cultures exhibited specific binding of l2fiI-insulin and were capable of degrading it. Insulin binding per cell was 2.4 and 10 fold higher in the subconfluent and modified cultures, respectively, as compared to the confluent cultures. Similarly, the rate of insulin degradation was higher in the subconfluent and nwdified cultures (2.3 and 20 fold, respectively). The increase in insulin binding and processing under conditions of cell growth suggests a role for insulin in the regulation of endothelial cell proliferation. However, insulin was found to stimulate DNA synthesis only in sparse, serum starved normal endothelial cells and not in the variant cells which lost the property of contact inhibition. This may imply a differential role for insulin in the regulation of growth in normal and transformed endothelial cells, which may result from a post-receptor defect in the variant cells.