Requirement for mevalonate in the control of proliferation of human breast cancer cells.
The proliferative rate as well as the activity of 3-hydroxy-3-methylglutaryl CoA (HMG CoA) reductase, which regulates de novo synthesis of mevalonate, was comparable in the two human breast cancer cell lines Hs578T and MDA-231 when cultured in the presence of serum. Upon treatment with mevinolin (an HMG CoA reductase inhibitor) the proliferation of the cell lines was depressed with similar dose response kinetics. A depression of the enzymatic activity to a level of 1-1.5 pmol mevalonate/min/mg protein decreased DNA-synthesis by approximately 90%. In contrast, at slightly higher enzymatic activities, ie 2-2.5 pmol/min/mg protein, there was only a mild decrease in DNA-synthesis. Addition of mevalonate to a final concentrations of 0.77 mM completely prevented the mevinolin-induced block on cell proliferation in both cell lines. Exposure to serum-free medium caused by itself a depression of HMG CoA reductase activity to 2.5-3 pmol/min/mg protein in both cell lines. Whereas the proliferation of MDA-231 was not inhibited at all by serum depletion, this treatment decreased DNA-synthesis in Hs578T by nearly 80%. Interestingly, the addition of mevalonate also prevented this growth inhibition in Hs578T, irrespective of whether mevinolin was present or not. However, this required a 30-fold increase in the mevalonate concentration (23.1 mM) as compared to MDA-231. The present data indicate that mevalonate is not only necessary for cell proliferation, but also that mevalonate is involved in the serum-dependent control of cell proliferation in serum-sensitive cells. In this respect, serum seems to affect the utilization of mevalonate in the formation of mevalonate-derived growth-regulatory molecules, rather than regulating the de novo synthesis of mevalonate.