{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T16:18:11Z","timestamp":1790957891341,"version":"4.1.0"},"reference-count":55,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2009,12,8]],"date-time":"2009-12-08T00:00:00Z","timestamp":1260230400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2010,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In neuroblastoma LAN\u20101 cells harboring an amplified <jats:italic>MycN<\/jats:italic> gene, disruption of cooperation between Ras and MycN proteins by the Ras inhibitor farnesylthiosalicylic acid (FTS, Salirasib) reportedly arrests cell growth. Our aim was to establish whether this is a general phenomenon. We examined the effects of FTS on gene\u2010expression profiles, growth and death of NCIH929 myeloma cells and K562 leukemia cells, which\u2014like LAN\u20101 cells\u2014exhibit <jats:italic>Myc<\/jats:italic> gene amplification and harbor active Ras. Under specified conditions, FTS reduced Ras and Myc and induced cell growth arrest and death in all <jats:italic>Myc<\/jats:italic>\u2010amplified cell lines but not in SHEP, a neuroblastoma cell line without <jats:italic>Myc<\/jats:italic> gene amplification. Gene\u2010expression analysis revealed a common pattern of FTS\u2010induced endoplasmic reticulum (ER) stress, known as the unfolded protein response (UPR), in <jats:italic>Myc<\/jats:italic>\u2010amplified cells, but not in SHEP. Thus, Ras negatively regulates ER stress in cells with amplified <jats:italic>Myc<\/jats:italic>. ER stress was also inducible by dominant\u2010negative (DN)\u2010Ras or shRNA to Ras isoforms, all of which induced an increase in BIP (the master regulator of ER stress) and its downstream targets Nrf2 and eIF2\u03b1, both regulated by active p\u2010PERK. FTS also induced an increase in p\u2010PERK, while small interfering RNA to PERK reduced Nrf2 and ATF4 and rescued cells from FTS\u2010induced death. BIP and its downstream targets were also increased by inhibitors of MAPK p38 and MEK. Ras, acting through MAPK p38 and MEK, negatively regulates the ER stress cascades BIP\/PERK\/Nrf2 and eIF2\u03b1\/ATF4\/ATF3. These findings can explain the Ras\u2010dependent protection of <jats:italic>Myc<\/jats:italic>\u2010amplified cells from ER stress\u2010associated death.<\/jats:p>","DOI":"10.1002\/ijc.25102","type":"journal-article","created":{"date-parts":[[2009,12,8]],"date-time":"2009-12-08T19:11:32Z","timestamp":1260299492000},"page":"2268-2281","source":"Crossref","is-referenced-by-count":23,"title":["Ras inhibits endoplasmic reticulum stress in human cancer cells with amplified 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