Salicylate-induced Growth Arrest Is Associated with Inhibition of p70s6kand Down-regulation of c-Myc, Cyclin D1, Cyclin A, and Proliferating Cell Nuclear Antigen

Brian K. Law, Mary E. Waltner-Law, Amelia J. Entingh, Anna Chytil, Mary E. Aakre, Peter Nørgaard, Harold L. Moses
2000 Journal of Biological Chemistry  
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
more » ... sferase 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 M) 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 salicylateinduced Thr 389 dephosphorylation. . 1 The abbreviations used are: COX1 and COX2, cyclooxygenases 1 and 2; PI 3-kinase, phosphatidylinositol 3-kinase; FTI, Merck peptidomimetic farnesyltransferase inhibitor L-744,832; PCNA, proliferating cell nuclear antigen; PMA, phorbol myristate acetate; Erk1/2, extracellular signal-regulated protein kinases 1 and 2, or conventional mitogenactivated protein kinase; MAPK, mitogen-activated protein kinase; NSAID, nonsteroidal anti-inflammatory drug; PDK1, 3Ј-phosphoinositide-dependent kinase-1; EGF, epidermal growth factor; IGF-1, insulinlike growth factor-1; PCR, polymerase chain reaction; mTOR, mammalian target of rapamycin.
doi:10.1074/jbc.m005545200 pmid:10993886 fatcat:7wxuvrlt35bnth2hwomeae6ydy