Abstract:
1-O-Octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (ET18-OCH$\sb3),$ a prototype of synthetic antitumor ether lipids (AEL), selectively inhibits the growth of a variety of cancer cells relative to normal cells. The mechanism of its antiproliferative action remains obscure. We have explored a number of hypotheses using five epithelial cancer cell lines (MCF-7, T84, A427, A549 and Malme 3M). Our studies have shown (1) that cellular ether lipid content or composition does not correlate with the sensitivity of the cells to the growth-inhibitory activity of ET18-OCH$\sb3$; (2) the observed effects of this ether compound on the cellular lipid metabolism do not underlie its antiproliferative action; (3) ET18-OCH$\sb3$, rather than its metabolite 1-O-octadecyl-2-O-methyl-sn-glycerol, is the main active compound responsible for the growth-inhibitory effect in sensitive cell lines (e.g., MCF-7); (4) ET18-OCH$\sb3$ inhibits the PKC-dependent phosphorylation of endogenous proteins following stimulation of quiescent MCF-7 cells with TPA or DAG; (5) ET18-OCH$\sb3$ truncates the EGF- or serum-induced activation of MAPK in quiescent MCF-7 cells via interference in the membrane association of Raf-1 that leads to inhibition of the Raf-1 kinase activity and of the phosphorylation of MEK as well as MAPK. A direct correlation between ET18-OCH$\sb3$ accumulation, inhibition of cell proliferation, Raf-1 association with the membrane, and MAPK activation has also been established. These results suggest that inhibition of the MAPK cascade as a result of its effect on Raf-1 activation, and inhibition of the PKC pathway may be important mechanisms by which ET18-OCH$\sb3$ inhibits cell proliferation.
