title: Sorafenib sensitizes hepatocellular carcinoma cells to physiological apoptotic stimuli.
abstract: Sorafenib increases survival rate of patients with advanced hepatocellular carcinoma (HCC). The mechanism underlying this effect is not completely understood. In this work we have analyzed the effects of sorafenib on autocrine proliferation and survival of different human HCC cell lines. Our results indicate that sorafenib in vitro counteracts autocrine growth of different tumor cells (Hep3B, HepG2, PLC-PRF-5, SK-Hep1). Arrest in S/G2/M cell cycle phases were observed coincident with cyclin D1 down-regulation. However, sorafenib's main anti-tumor activity seems to occur through cell death induction which correlated with caspase activation, increase in the percentage of hypodiploid cells, activation of BAX and BAK and cytochrome c release from mitochondria to cytosol. In addition, we observed a rise in mRNA and protein levels of the pro-apoptotic "BH3-domain only" PUMA and BIM, as well as decreased protein levels of the anti-apoptotic MCL1 and survivin. PUMA targeting knock-down, by using specific siRNAs, inhibited sorafenib-induced apoptotic features. Moreover, we obtained evidence suggesting that sorafenib also sensitizes HCC cells to the apoptotic activity of transforming growth factor-β (TGF-β) through the intrinsic pathway and to tumor necrosis factor-α (TNF) through the extrinsic pathway. Interestingly, sensitization to sorafenib-induced apoptosis is characteristic of liver tumor cells, since untransformed hepatocytes did not respond to sorafenib inducing apoptosis, either alone or in combination with TGF-β or TNF. Indeed, sorafenib effectiveness in delaying HCC late progression might be partly related to a selectively sensitization of HCC cells to apoptosis by disrupting autocrine signals that protect them from adverse conditions and pro-apoptotic physiological cytokines.
authors: Biological Clues of the Invasive and Metastatic Phenotype Group, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
authors: Joan
authors: J
authors: Fernando
authors: Patricia
authors: P
authors: Sancho
authors: Conrado M
authors: CM
authors: Fernández-Rodriguez
authors: José L
authors: JL
authors: Lledó
authors: Laia
authors: L
authors: Caja
authors: Jean S
authors: JS
authors: Campbell
authors: Nelson
authors: N
authors: Fausto
authors: Isabel
authors: I
authors: Fabregat
references: Oncogene. 2009 Jun 18;28(24):2348-57
references: 19421143
references: J Hepatol. 2009 Oct;51(4):725-33
references: 19665249
references: World J Gastroenterol. 2009 Feb 7;15(5):513-20
references: 19195051
references: Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5408-12
references: 1608949
references: Clin Cancer Res. 2010 Jan 15;16(2):390-7
references: 20068087
references: Cancer Res. 2009 May 1;69(9):3927-36
references: 19366808
references: J Hepatol. 2011 Nov;55(5):1041-8
references: 21354226
references: Oncogene. 2005 Oct 20;24(46):6861-9
references: 16007148
references: Biochem Pharmacol. 2008 May 15;75(10):1935-45
references: 18371937
references: Endocr Rev. 2007 Jun;28(4):365-86
references: 17431229
references: J Cell Physiol. 2009 Jul;220(1):214-21
references: 19288493
references: Cell Death Differ. 2004 Jul;11 Suppl 1:S86-96
references: 15105837
references: N Engl J Med. 2008 Jul 24;359(4):378-90
references: 18650514
references: Cancer Res. 1986 May;46(5):2330-4
references: 3008986
references: Mol Cancer Ther. 2008 Oct;7(10):3129-40
references: 18852116
references: Hepatology. 2003 Nov;38(5):1095-106
references: 14578848
references: Semin Cancer Biol. 2011 Feb;21(1):4-9
references: 20851183
references: Cancer Res. 2009 Oct 1;69(19):7595-602
references: 19773433
references: FASEB J. 2001 Mar;15(3):741-51
references: 11259392
references: Cancer Res. 2010 Nov 15;70(22):9309-18
references: 21062976
references: Cancer Res. 2006 Dec 15;66(24):11851-8
references: 17178882
references: Clin Cancer Res. 2010 Nov 1;16(21):5189-99
references: 20884624
references: J Hepatol. 2011 Aug;55(2):351-8
references: 21147185
references: Mol Cancer Res. 2002 Nov;1(1):68-78
references: 12496370
references: Am J Pathol. 2007 Dec;171(6):1831-46
references: 17991716
references: Cancer Cell. 2007 Jul;12(1):66-80
references: 17613437
references: Oncogene. 2008 Dec;27 Suppl 1:S71-83
references: 19641508
references: J Biol Chem. 2009 Sep 25;284(39):26591-602
references: 19638343
references: J Hepatol. 2010 Jan;52(1):79-87
references: 19910069
references: Annu Rev Med. 2010;61:317-28
references: 20059340
references: Exp Cell Res. 1992 Oct;202(2):495-500
references: 1397101
references: Cancer Res. 1991 Aug 1;51(15):4080-3
references: 1649698
references: Cell. 2010 Jan 22;140(2):197-208
references: 20141834
references: Expert Opin Investig Drugs. 2010 May;19(5):615-29
references: 20374038
references: Mol Cell Biol. 2007 Aug;27(15):5499-513
references: 17548474
references: Hepatology. 2009 Dec;50(6):1861-70
references: 19821497
references: Hepatology. 2006 Oct;44(4):1012-24
references: 17006932
references: Hepatology. 2000 May;31(5):1080-5
references: 10796883
references: J Cell Physiol. 2010 Jul;224(1):112-9
references: 20301194
references: Leukemia. 2008 Apr;22(4):808-18
references: 18200035
references: Hepatology. 2010 Oct;52(4):1310-21
references: 20799354
references: Cancer Res. 2006 Feb 1;66(3):1611-9
references: 16452220
references: J Biol Chem. 1996 Mar 29;271(13):7416-22
references: 8631767
references: Clin Cancer Res. 2008 Sep 1;14(17):5385-99
references: 18765530
references: Clin Cancer Res. 2009 Sep 15;15(18):5820-8
references: 19737956