ET-18-OCH3 Inhibits the Phosphorylation and Activation of p70 S6 Kinase in MCF-7 Cells

• Published in: Anticancer research Vol. 25; no. 1A; pp. 95 - 100
• Main Authors: ARTHUR, Gilbert, SAMADDER, Pranati, BITTMAN, Robert
• Format: Journal Article
• Language: English
• Published: Attiki International Institute of Anticancer Research 01.01.2005
• Subjects: Antineoplastic Agents - pharmacology; Biological and medical sciences; Breast Neoplasms - enzymology; Breast Neoplasms - pathology; Cell Growth Processes - drug effects; Cell Growth Processes - physiology; Cell Line, Tumor; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Humans; Medical sciences; Phosphatidylinositol 3-Kinases - metabolism; Phospholipid Ethers - pharmacology; Phosphorylation - drug effects; Ribosomal Protein S6 Kinases, 70-kDa - antagonists & inhibitors; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Tetradecanoylphorbol Acetate - pharmacology; Tumors; Phosphorylation; Cancerology; Ether; Enzyme; Kinase; Transferases; Ether lipids. ET-18-OCH3. MCF-7 cells; Lipids; Inhibitor; p70 S6 kinase
• ISSN: 0250-7005; 1791-7530

Alkyllysophospholipids (ALPs) inhibit the proliferation of epithelial cancer cells, and may achieve this by perturbing a number of intracellular signaling pathways. p70 S6 kinase (p70 S6K ) is a key intracellular signaling molecule in the regulation of cell proliferation. We therefore investigated whether ALPs inhibit p70 S6K 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-OCH 3 ), inhibits the activation of p70 S6K in MCF-7 cells but does not inhibit the activity of p70 S6K . Inhibition of activation is achieved by preventing the phosphorylation of Thr 389 , Thr 421 , Ser 424 and Ser 411 residues of p70 S6K , which are required for full activation of the kinase. ET-18-OCH 3 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 p70 S6K , which was sensitive to the m-Tor inhibitor but not the phosphoinositide 3-kinase inhibitor, was also inhibited by ET-18-OCH 3 . Hence the diminished phosphorylation of p70 S6K by ET-18-OCH 3 is a result of the inhibition of both phosphoinositide 3-kinase-dependent and -independent activation of p70 S6K . The differential effects of ENE-OCH 3 , a phosphonocholine analog of ET-18-OCH 3 , on MCF-7 cell proliferation correlated with its effects on p70 S6K activation. The data suggest that the inhibition of p70 S6K activation of by ET-18-OCH 3 contributes to the antiproliferative effects of ALPs in MCF-7 cells.