Agnes Balogh

Gonadotropin-releasing hormone analogues inhibit cell proliferation and activate signal transduction pathways in MDA-MB-231 human breast cancer cell line

A novel gonadotropin-releasing hormone (GnRH) agonist (folligen) which stimulates follicular maturation has been developed in our laboratory. The direct effect of folligen and a well-known superactive GnRH analogue, buserelin, on the MDA-MB-231 human breast cancer cell line was investigated. Folligen was found to be slightly more active in inhibiting cell proliferation than buserelin, and significant differences were found in the signal transduction pathways activated by these analogues. These results demonstrate for the first time that tyrosine kinases and/or phospholipid turnover together with protein kinase C activation can be directly involved in the antitumor activity of GnRH analogues. The results also suggest that folligen and buserelin might have a different mechanism of action on this human breast cancer cell line.

Phosphatidylcholine could be the source of 1,2-DAG which activates protein kinase C in EGF-stimulated colon carcinoma cells (HT29)

In our previous study (A. Balogh et al, Cell. Signalling 5 (6), 795-802, 1993.), we have shown that epidermal growth factor (EGF) increased protein kinase C (PKC) activities in colon carcinoma cell line (HT29), possibly through the increased 1,2-diacylglycerol (1,2-DAG) production via phosphatidylcholine (PC). Here we investigate the effect of well-known PKC activator 12-O-tetradecanoyl-2 phorbol-13-acetate (TPA), on the levels of 32P incorporation into EGF induced phosphatidylinositols (PI, PI4P, PI4, 5P2) and different phospholipids (PC, PA, PS) as well as on induced tyrosine kinase activity. TPA significantly decreased the effects of EGF and it had the biggest inhibitory effect on EGF induced PC level. These data support our contention that PC plays an important role in the activation of PKC via 1,2-DAG production in the EGF stimulated pathway.

Comparison of the Tyrosine Kinase Activity with the Proliferation Rate in Human Colon Solid Tumors and Tumor Cell Lines

The role of the tyrosine kinase signal transduction pathway was investigated in human colon solid tumors and colon tumor cell lines. A high level of tyrosine kinase activity was found in 7 of the 27 human solid tumors tested (26%). In these cases, a close correlation between the level of tyrosine kinase activity and the high ratio of the S phase cells has been demonstrated (r = 0.8418). High autophosphorylation accompanied by a high proliferation capacity was detected in 8 cases (29.6%). In 12 cases (44%) low tyrosine kinase activity with a lower proliferation rate was found. Seven of the 8 human colon tumor cell lines tested showed tyrosine kinase activity. Differentiation-inducing agents, such as sodium butyrate and retinoic acid, have been applied to influence the rate of cell proliferation. Treatment with 5 mM sodium butyrate (24 h) and 10 microM retinoic acid (48 h) effectively decreased the fraction of S phase cells and 3H-thymidine incorporation. The tyrosine kinase activity fell to 9-22% and to 44-65% of the original value in the case of the sodium butyrate and retinoic acid treatment, respectively. Our results suggest that a significant part of human colon tumors have an active tyrosine kinase signal transduction pathway and that tyrosine kinase plays a role in the process of proliferation rather than in the process of differentiation in these human colon tumor cell lines.