Salicylate-induced growth arrest is associated with inhibition of p70(s6k)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 th eir analgesic and anti-inflammatory properties, and more recently for their ability to protect against colon cancer and cardiovascular disease, Despit e the wide use of salicylate, the mechanisms underlying its biological acti vities are largely unknown. Recent reports suggest that salicylate may prod uce some of its effects by modulating the activities of protein kinases. Si nce we have previously shown that the farnesyltransferase inhibitor L-744,8 32 inhibits cell proliferation and p70(s6k) activity, and salicylate inhibi ts cell proliferation, we examined whether salicylate affects p70(s6k) acti vity. We find that salicylate potently inhibits p70(s6k) activation and pho sphorylation in a p38 MAPK-independent manner. Interestingly, low salicylat e concentrations (less than or equal to 250 muM) inhibit p70(s6k) activatio n by phorbol myristate acetate, while higher salicylate concentrations (gre ater than or equal to5 mM) are required to block p70(s6k) activation by epi dermal growth factor + insulin-like growth factor-1, These data suggest tha t salicylate may selectively inhibit p70(s6k) activation in response to spe cific stimuli. Inhibition of p70(s6k) by salicylate occurs within 5 min, is independent of the phosphatidylinositol 3-kinase pathway, and is associate d with dephosphorylation of p70(s6k) on its major rapamycin-sensitive site, Thr(389). A rapamycin-resistant mutant of p70(s6k) is resistant to salicyl ate-induced Thr(389) dephosphorylation.