PMID- 21618507 OWN - NLM STAT- MEDLINE DCOM- 20120608 LR - 20211203 IS - 1097-0215 (Electronic) IS - 0020-7136 (Print) IS - 0020-7136 (Linking) VI - 130 IP - 7 DP - 2012 Apr 1 TI - Dual inhibition of phosphatidylinositol 3-kinase/Akt and mammalian target of rapamycin signaling in human nonsmall cell lung cancer cells by a dietary flavonoid fisetin. PG - 1695-705 LID - 10.1002/ijc.26178 [doi] AB - 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-kinase (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-dependent 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-4E and 4E-BP1. Fisetin-treated cells also exhibited dose-dependent inhibition of the constituents of mTOR signaling complex such as Rictor, Raptor, GbetaL and PRAS40. There was an increase in the phosphorylation of AMPKalpha 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-siRNA 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. CI - Copyright (c) 2011 UICC. FAU - Khan, Naghma AU - Khan N AD - Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA. FAU - Afaq, Farrukh AU - Afaq F FAU - Khusro, Fatima H AU - Khusro FH FAU - Mustafa Adhami, Vaqar AU - Mustafa Adhami V FAU - Suh, Yewseok AU - Suh Y FAU - Mukhtar, Hasan AU - Mukhtar H LA - eng GR - R03 CA153961-01A1/CA/NCI NIH HHS/United States GR - R03CA153961/CA/NCI NIH HHS/United States GR - R01 CA120451-05/CA/NCI NIH HHS/United States GR - R03 CA153961/CA/NCI NIH HHS/United States GR - R01 CA120451/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20110826 PL - United States TA - Int J Cancer JT - International journal of cancer JID - 0042124 RN - 0 (AKT1S1 protein, human) RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Carrier Proteins) RN - 0 (Cell Cycle Proteins) RN - 0 (EIF4EBP1 protein, human) RN - 0 (Eukaryotic Initiation Factor-4E) RN - 0 (Flavonoids) RN - 0 (Flavonols) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (MLST8 protein, human) RN - 0 (Phosphoinositide-3 Kinase Inhibitors) RN - 0 (Phosphoproteins) RN - 0 (RICTOR protein, human) RN - 0 (RPTOR protein, human) RN - 0 (Rapamycin-Insensitive Companion of mTOR Protein) RN - 0 (Regulatory-Associated Protein of mTOR) RN - 0 (TSC2 protein, human) RN - 0 (Tuberous Sclerosis Complex 2 Protein) RN - 0 (Tumor Suppressor Proteins) RN - 0 (mTOR Associated Protein, LST8 Homolog) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases) RN - EC 3.1.3.67 (PTEN Phosphohydrolase) RN - OO2ABO9578 (fisetin) SB - IM MH - AMP-Activated Protein Kinase Kinases MH - Adaptor Proteins, Signal Transducing/antagonists & inhibitors/metabolism MH - Carcinoma, Non-Small-Cell Lung/*drug therapy/metabolism MH - Carrier Proteins/antagonists & inhibitors/metabolism MH - Cell Cycle Proteins MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - Eukaryotic Initiation Factor-4E/antagonists & inhibitors/metabolism MH - Flavonoids/*pharmacology MH - Flavonols MH - Humans MH - Intracellular Signaling Peptides and Proteins/antagonists & inhibitors/metabolism MH - Lung Neoplasms/*drug therapy/enzymology/metabolism MH - PTEN Phosphohydrolase/metabolism MH - Phosphatidylinositol 3-Kinase/metabolism MH - *Phosphoinositide-3 Kinase Inhibitors MH - Phosphoproteins/antagonists & inhibitors/metabolism MH - Phosphorylation/drug effects MH - Protein Kinases/metabolism MH - Proto-Oncogene Proteins c-akt/*antagonists & inhibitors/metabolism MH - Rapamycin-Insensitive Companion of mTOR Protein MH - Regulatory-Associated Protein of mTOR MH - Ribosomal Protein S6 Kinases, 70-kDa/antagonists & inhibitors/metabolism MH - Stem Cells/drug effects MH - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism MH - Tuberous Sclerosis Complex 2 Protein MH - Tumor Cells, Cultured MH - Tumor Suppressor Proteins/antagonists & inhibitors/metabolism MH - mTOR Associated Protein, LST8 Homolog PMC - PMC3267899 MID - NIHMS320341 EDAT- 2011/05/28 06:00 MHDA- 2012/06/09 06:00 PMCR- 2013/04/01 CRDT- 2011/05/28 06:00 PHST- 2011/03/21 00:00 [received] PHST- 2011/05/03 00:00 [accepted] PHST- 2011/05/28 06:00 [entrez] PHST- 2011/05/28 06:00 [pubmed] PHST- 2012/06/09 06:00 [medline] PHST- 2013/04/01 00:00 [pmc-release] AID - 10.1002/ijc.26178 [doi] PST - ppublish SO - Int J Cancer. 2012 Apr 1;130(7):1695-705. doi: 10.1002/ijc.26178. Epub 2011 Aug 26.