COORDINATED INCREASE IN ACTIVITIES OF THE SIGNAL-TRANSDUCTION ENZYMESPI-KINASE AND PIP-KINASE IN HUMAN CANCER-CELLS

The steady-state activities of the first two enzymes of the phosphatid ylinositol (PI) phosphorylation pathway, PI 4-kinase, EC 2.7.1.67 (PI kinase) and PI 4-phosphate 5-kinase, EC 2.7.1.68 (PIP kinase) as compa red to human normal ovary are elevated in human ovarian carcinomas (4. 1- and 2.7-fold) and in human OVCAR-5 cells in tissue culture (31.2- a nd 8.9-fold). Compared to normal human breast parenchymal cells, PI ki nase and PIP kinase activities were increased in breast carcinoma MDA- MB-435 cells grown in nude mice as solid tumors (7.3- and 2.3-fold, re spectively) and in MDA-MB-435 cells grown in tissue culture (95.8- and 15.5-fold, respectively). When the human carcinoma cells were plated and expressed their neoplastic proliferative program in the log phase, in the MDA-MB-435 breast carcinoma cells the PI and PIP kinase activi ties coordinately increased 11-fold; in ovarian carcinoma OVCAR-5 cell s 5.8- and 4.5-fold, respectively. These studies provide the first evi dence in human cancer cells of an increased capacity for the operation of signal transduction. This is indicated by the markedly elevated ac tivities of PI and PIP kinases in the phosphatidylinositol phosphoryla tion sequence which leads to production of second messengers, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).