{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T09:20:43Z","timestamp":1789896043572,"version":"4.0.1"},"reference-count":46,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2011,8,26]],"date-time":"2011-08-26T00:00:00Z","timestamp":1314316800000},"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":[[2012,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Lung cancer is one of the most commonly occurring malignancies. It has been reported that mammalian target of rapamycin (mTOR) is phosphorylated in lung cancer and its activation was more frequent in tumors with overexpression of phosphatidylinositol 3\u2010kinase (PI3K)\/Akt. Therefore, dual inhibitors of PI3K\/Akt and mTOR signaling could be valuable agents for treating lung cancer. In the present study, we show that fisetin, a dietary tetrahydroxyflavone inhibits cell growth with the concomitant suppression of PI3K\/Akt and mTOR signaling in human nonsmall cell lung cancer (NSCLC) cells. Using autodock 4, we found that fisetin physically interacts with the mTOR complex at two sites. Fisetin treatment was also found to reduce the formation of A549 cell colonies in a dose\u2010dependent manner. Treatment of cells with fisetin caused decrease in the protein expression of PI3K (p85 and p110), inhibition of phosphorylation of Akt, mTOR, p70S6K1, eIF\u20104E and 4E\u2010BP1. Fisetin\u2010treated cells also exhibited dose\u2010dependent inhibition of the constituents of mTOR signaling complex such as Rictor, Raptor, G\u03b2L and PRAS40. There was an increase in the phosphorylation of AMPK\u03b1 and a decrease in the phosphorylation of TSC2 on treatment of cells with fisetin. We also found that treatment of cells with mTOR inhibitor rapamycin and mTOR\u2010siRNA caused decrease in phosphorylation of mTOR and its target proteins which were further downregulated on treatment with fisetin, suggesting that these effects are mediated in part, through mTOR signaling. Our results show that fisetin suppressed PI3K\/Akt and mTOR signaling in NSCLC cells and thus, could be developed as a chemotherapeutic agent against human lung cancer.<\/jats:p>","DOI":"10.1002\/ijc.26178","type":"journal-article","created":{"date-parts":[[2011,5,26]],"date-time":"2011-05-26T10:20:52Z","timestamp":1306405252000},"page":"1695-1705","source":"Crossref","is-referenced-by-count":144,"title":["Dual inhibition of phosphatidylinositol 3\u2010kinase\/Akt and mammalian target of rapamycin signaling in human nonsmall cell lung cancer cells by a dietary flavonoid fisetin"],"prefix":"10.1002","volume":"130","author":[{"given":"Naghma","family":"Khan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farrukh","family":"Afaq","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima 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