title: 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.
abstract: 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, GβL and PRAS40. There was an increase in the phosphorylation of AMPKα 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.
authors: Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA.
authors: Naghma
authors: N
authors: Khan
authors: Farrukh
authors: F
authors: Afaq
authors: Fatima H
authors: FH
authors: Khusro
authors: Vaqar
authors: V
authors: Mustafa Adhami
authors: Yewseok
authors: Y
authors: Suh
authors: Hasan
authors: H
authors: Mukhtar
references: J Biol Chem. 2002 Sep 20;277(38):35364-70
references: 12167664
references: Science. 1997 Mar 28;275(5308):1943-7
references: 9072974
references: Acta Pharmacol Sin. 2005 Oct;26(10):1253-8
references: 16174443
references: J Cell Biol. 2004 Jul 19;166(2):213-23
references: 15249583
references: Cancer Cell. 2005 Sep;8(3):179-83
references: 16169463
references: Nat Rev Drug Discov. 2006 Aug;5(8):671-88
references: 16883305
references: J Nutr. 2000 Sep;130(9):2243-50
references: 10958819
references: Int J Cancer. 2009 Nov 15;125(10):2465-73
references: 19670328
references: J Biol Chem. 2002 Jul 12;277(28):25226-32
references: 11994296
references: Carcinogenesis. 2009 Feb;30(2):300-7
references: 19037088
references: Biochem Biophys Res Commun. 2004 Aug 13;321(1):161-7
references: 15358229
references: Oncologist. 2008 Feb;13(2):139-47
references: 18305058
references: Cancer Res. 2000 Jul 1;60(13):3504-13
references: 10910062
references: Oncogene. 2008 Jan 24;27(5):585-95
references: 17684489
references: Drug Resist Updat. 2008 Feb-Apr;11(1-2):32-50
references: 18166498
references: Hum Mol Genet. 2005 Oct 15;14 Spec No. 2:R251-8
references: 16244323
references: Curr Opin Pharmacol. 2008 Jun;8(3):267-74
references: 18394961
references: Semin Cell Dev Biol. 2005 Feb;16(1):29-37
references: 15659337
references: Nat Rev Cancer. 2002 Jul;2(7):489-501
references: 12094235
references: Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16568-73
references: 17050681
references: Nat Med. 2004 May;10(5):484-6
references: 15098029
references: Curr Opin Oncol. 2004 Nov;16(6):564-75
references: 15627018
references: Mol Pharmacol. 2007 Jun;71(6):1703-14
references: 17387141
references: Exp Cell Res. 2001 Mar 10;264(1):29-41
references: 11237521
references: Cancer Cell. 2007 Jul;12(1):9-22
references: 17613433
references: Oncogene. 2006 Oct 16;25(48):6423-35
references: 17041627
references: J Clin Invest. 2007 Mar;117(3):730-8
references: 17290308
references: Carcinogenesis. 2010 Aug;31(8):1424-33
references: 20530556
references: Annu Rev Biochem. 1998;67:821-55
references: 9759505
references: Arch Toxicol. 2002 Jun;76(5-6):351-9
references: 12107653
references: Trends Biochem Sci. 2004 Jan;29(1):32-8
references: 14729330
references: CA Cancer J Clin. 2010 Sep-Oct;60(5):277-300
references: 20610543
references: Prostate Cancer Prostatic Dis. 2006;9(1):68-76
references: 16314891
references: Int J Oncol. 2001 Jun;18(6):1175-9
references: 11351248
references: Curr Biol. 2001 Jul 10;11(13):R502
references: 11470419
references: Nat Rev Cancer. 2004 May;4(5):335-48
references: 15122205
references: Cancer Res. 2006 Feb 1;66(3):1500-8
references: 16452206
references: Cancer Res. 2008 Oct 15;68(20):8555-63
references: 18922931
references: Clin Cancer Res. 2002 Oct;8(10):3046-53
references: 12374671
references: Carcinogenesis. 2008 May;29(5):1049-56
references: 18359761
references: Trends Pharmacol Sci. 2005 Feb;26(2):69-76
references: 15681023
references: Recent Pat Anticancer Drug Discov. 2010 Jan;5(1):29-57
references: 19751211
references: Clin Cancer Res. 2006 Jul 15;12(14 Pt 2):4365s-4371s
references: 16857812
references: J Biol Chem. 1995 Jan 13;270(2):815-22
references: 7822316
references: Oncogene. 2004 Apr 19;23(18):3189-99
references: 15094768
references: J Invest Dermatol. 2011 Jun;131(6):1291-9
references: 21346776