Salicylate-induced growth arrest is associated with inhibition of p70s6k and down-regulation of c-myc, cyclin D1, cyclin A, and proliferating cell nuclear antigen.
Salicylate and its pro-drug form aspirin are widely used medicinally for their analgesic and anti-inflammatory properties, and more recently for their ability to protect against colon cancer and cardiovascular disease. Despite the wide use of salicylate, the mechanisms underlying its biological activities are largely unknown. Recent reports suggest that salicylate may produce some of its effects by modulating the activities of protein kinases. Since we have previously shown that the farnesyltransferase inhibitor l-744, 832 inhibits cell proliferation and p70(s6k) activity, and salicylate inhibits cell proliferation, we examined whether salicylate affects p70(s6k) activity. We find that salicylate potently inhibits p70(s6k) activation and phosphorylation in a p38 MAPK-independent manner. Interestingly, low salicylate concentrations (</=250 microm) inhibit p70(s6k) activation by phorbol myristate acetate, while higher salicylate concentrations (>/=5 mm) are required to block p70(s6k) activation by epidermal growth factor + insulin-like growth factor-1. These data suggest that salicylate may selectively inhibit p70(s6k) activation in response to specific stimuli. Inhibition of p70(s6k) by salicylate occurs within 5 min, is independent of the phosphatidylinositol 3-kinase pathway, and is associated with dephosphorylation of p70(s6k) on its major rapamycin-sensitive site, Thr(389). A rapamycin-resistant mutant of p70(s6k) is resistant to salicylate-induced Thr(389) dephosphorylation.
Law
B K
BK
Vanderbilt Ingram Cancer Center, Department of Cell Biology, and Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, Tennessee 37232, USA.
Waltner-Law
M E
ME
Entingh
A J
AJ
Chytil
A
A
Aakre
M E
ME
Nørgaard
P
P
Moses
H L
HL
D000082:Acetaminophen / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D019925:Cyclin A / Q000235:genetics*; D019938:Cyclin D1 / Q000235:genetics*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D016259:Genes, myc; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors*; D012459:Salicylates / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D019925:Cyclin A; D018809:Proliferating Cell Nuclear Antigen; D016271:Proto-Oncogene Proteins c-myc; D012459:Salicylates; D019938:Cyclin D1; D000082:Acetaminophen; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D019893:Ribosomal Protein S6 Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate; D001241:Aspirin; D007213:Indomethacin