Mechanism of inhibition of MCF-7 cell proliferation by alkyllysophospholipids (ALPs)

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Richard, Christina
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Alkyllysophospholipids (ALPs) are ether analogs of pysophosphatidylcholine that display antitumour properties in vitro and in vivo. The mechanism of its antiproliferative actions remains unknown. Previous studies have shown that 1-O-octadecyl-2-O-methylglycerophosphocholine (ET-18-OCH$\sb3$), the prototype ALP, inhibited MCF-7 cell proliferation by interfering in the activation of Raf-1 by perturbing the association of Raf-1 with the cell membrane. This consequently led to inhibition of mitogen-activated protein kinase (MAPK) and ultimately resulted in inhibition of cell growth. The objective of this study was to investigate whether the inhibition of Raf-1 activation by ET-18-OCH$\sb3$ was sufficient to completely inhibit the growth of MCF-7 cells. We examined the effects of ET-18-OCH3 on the multiple diverging signalling pathways activated following insulin stimulation. In order to determine whether inhibitions are causal to the decrease in cell growth, we examined the effect of two enantiomeric ALPs, (R)-and (S)-2'- (trimethylammonio)-ethyl-4-(hexadecyloxy)-3-methoxy-1- butenephosphonate (TDB-PC), with a differential effect on cell proliferation and MAPK activation, on the activation of PKB and p70 S6K. Taken together, our studies show that ET-18-OCH$\sb3$ inhibits the association of Raf-1 with the membrane by inhibiting the association of Raf-1 with Ras. In addition to the inhibition of Raf-1 association with the membrane, the inhibition of the PI3K pathway by ET-18-OCH$\sb3$ appears to also contribute to the inhibition of cell proliferation. (Abstract shortened by UMI.)