ET-18-OCH3 inhibits the phosphorylation and activation of p70 S6 kinase in MCF-7 cells.
Alkyllysophospholipids (ALPs) inhibit the proliferation of epithelial cancer cells, and may achieve this by perturbing a number of intracellular signaling pathways. p70 S6 kinase (p70S6K) is a key intracellular signaling molecule in the regulation of cell proliferation. We therefore investigated whether ALPs inhibit p70S6K activity and, if so, whether this may be relevant in the mechanism of inhibition of cell proliferation by ALPs. In this study, we demonstrated that the prototypic ALP, 1-O-octadecyl-2-O-methyl-rac-glycerophosphocholine (ET-18-OCH3), inhibits the activation of p70S6K in MCF-7 cells but does not inhibit the activity of p70S6K. Inhibition of activation is achieved by preventing the phosphorylation of Thr389, Thr421, Ser424 and Ser411 residues of p70S6K, which are required for full activation of the kinase. ET-18-OCH3 inhibited insulin-stimulated activation of MCF-7 cells, which is sensitive to the phosphoinositide 3-kinase inhibitor LY294002, and to the m-Tor inhibitor rapamycin. Phorbol ester-induced activation of p70S6K which was sensitive to the m-Tor inhibitor but not the phosphoinositide 3-kinase inhibitor, was also inhibited by ET-18-OCH3. Hence the diminished phosphorylation of p70S6K by ET-18-OCH3 is a result of the inhibition of both phosphoinositide 3-kinase-dependent and -independent activation of p70S6K. The differential effects of ENE-OCH3, a phosphonocholine analog of ET-18-OCH3, on MCF-7 cell proliferation correlated with its effects on p70S6K activation. The data suggest that the inhibition of p70S6K activation of by ET-18-OCH3 contributes to the antiproliferative effects of ALPs in MCF-7 cells.
Arthur
Gilbert
G
Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada R3E 0W3. arthurg@ms.umanitoba.ca
Samadder
Pranati
P
Bittman
Robert
R
D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010742:Phospholipid Ethers / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010742:Phospholipid Ethers; C026659:edelfosine; D019869:Phosphatidylinositol 3-Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D013755:Tetradecanoylphorbol Acetate