Amplified increase in signal transduction activity in cancer cells

To elucidate the behavior of 1 phosphatidylinositol 4,5 bisphosphate (PIP2) 5 phosphatase (PIP2 5-Pase, EC 3.1.3.36) and 1 phosphatidylinositol 4 phosphate (PIP) 4-phosphatase (PIP 4-Pase) in cancer cells, the steady state activities of PIP2 5-Pase and PIP 4-Pase were determined in the particulate fractions of rat liver and in a spectrum of rat hepatomas of different growth rates and malignancy.

A standard method was developed using exogenous PIP2 or PIP as substrates.

One half of the maximum activities was reached at about 0.3 mM of the substrates and at 0.1 to 0.2 mM magnesium chloride. The optimum concentrations of Triton X-100 and cetyltrimethyl ammonium bromide were 0.25% (w/v) and 1 mM, respectively. PIP2 5-Pase and PIP 4-Pase activities were linear with time for 20 min and proportional with protein concentrations up to 22 micrograms per 50 microliters reaction mixture. In rat liver the steady state activities of PIP2 5-Pase and PIP 4-Pase were 1849 to 1881 and 1394 to 1670 nmol/h/mg protein. In three rat hepatomas the enzyme activities decreased to 50-51% and 33-42%, respectively. These results and our earlier data showing increased 1 phosphatidylinositol 4 kinase (EC 2.7.1.67), PIP 5-kinase (EC 2.7.1.68) and phospholipase C, PIP2 phosphodiesterase (EC 3.1.4.11) activities provide evidence of a transformation linked amplified increased capacity in signal transduction activity in cancer cells. The discovery and documentation of this integrated imbalance in regulation in phosphoinositide metabolism in cancer cells are in line with our observations in cancer cells for enzymes of purine and pyrimidine metabolism. The amplified increase in signal transduction capacity in cancer cells provides novel targets for the development of anticancer drugs.