Farnesylthiosalicylic acid blocks mammalian target of rapamycin signaling in breast cancer cells.
Estradiol (E2) stimulates proliferation of hormone-dependent breast cancer and exerts downstream effects on growth factors and their receptors. Key among the pathways' mediating growth factor action is the MAP kinase signaling cascade and the PI-3 kinase pathway with its downstream effector mTOR. We postulated that farnesylthiosalicylic acid (FTS), a novel anti-Ras drug, could effectively inhibit hormone-dependent breast cancer because Ras activates both the MAP kinase and the PI3 kinase pathways. Wild-type MCF-7 cells and a long-term estrogen-deprived subline (LTED) were used to examine the effect of FTS on cell growth and on several biochemical parameters. FTS inhibited growth of both cell lines by reducing proliferation and inducing apoptosis. These effects correlated best with blockade of phosphorylation of PHAS-I and p70 S6 kinase, 2 downstream effectors of mTOR. We observed only minimal inhibition of Akt, an effector upstream of mTOR. Taken together, these findings demonstrate a novel effect of FTS to inhibit mTOR signaling and also suggest that mTOR has a key role in breast cancer cell proliferation. Unexpectedly, only minimal inhibition of MAP kinase occurred in response to FTS at concentrations that markedly reduced cell growth. These later data provide support for the concept that FTS exerts its effects predominantly by blocking mTOR and to a lesser effect by inhibition of MAP kinase in breast cancer cells.
Yue
Wei
W
Department of Internal Medicine, University of Virginia Health System, Charlovttesville, VA 22903, USA. wy9c@virginia.edu
Wang
Jiping
J
Li
Yuebai
Y
Fan
Ping
P
Santen
Richard J
RJ
D017209:Apoptosis / Q000187:drug effects; D001769:Blood; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004261:DNA Replication / Q000187:drug effects; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D005204:Farnesol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D012459:Salicylates / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases
D004815:Epidermal Growth Factor; D004958:Estradiol; D005204:Farnesol; D007334:Insulin-Like Growth Factor I; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D019893:Ribosomal Protein S6 Kinases; D012459:Salicylates; D058570:TOR Serine-Threonine Kinases; C093323:farnesylthiosalicylic acid; C546842:MTOR protein, human