Cellular senescence provides a biological barrier against tumor progression, often associated with oncogene-induced replication and/or oxidative stress, cytokine production and DNA damage response (DDR), leading to persistent cell-cycle arrest. While cytokines such as tumor necrosis factor-alpha (TNFα) and interferon gamma (IFNγ) are important components of senescence-associated secretome and induce senescence in, for example, mouse pancreatic β-cancer cell model, their downstream signaling pathway(s) and links with oxidative stress and DDR are mechanistically unclear. Using human and mouse normal and cancer cell models, we now show that TNFα and IFNγ induce NADPH oxidases Nox4 and Nox1, reactive oxygen species (ROS), DDR signaling and premature senescence. Unlike mouse tumor cells that required concomitant presence of IFNγ and TNFα, short exposure to IFNγ alone was sufficient to induce Nox4, Nox1 and DDR in human cells. siRNA-mediated knockdown of Nox4 but not Nox1 decreased IFNγ-induced DDR. The expression of Nox4/Nox1 required Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling and the effect was mediated by downstream activation of transforming growth factor-beta (TGFβ) secretion and consequent autocrine/paracrine activation of the TGFβ/Smad pathway. Furthermore, the expression of adenine nucleotide translocase 2 (ANT2) was suppressed by IFNγ contributing to elevation of ROS and DNA damage. In contrast to mouse B16 cells, inability of TC-1 cells to respond to IFNγ/TNFα by DDR and senescence correlated with the lack of TGFβ and Nox4 response, supporting the role of ROS induced by NADPH oxidases in cytokine-induced senescence. Overall, our data reveal differences between cytokine effects in mouse and human cells, and mechanistically implicate the TGFβ/SMAD pathway, via induction of NADPH oxidases and suppression of ANT2, as key mediators of IFNγ/TNFα-evoked genotoxicity and cellular senescence.

Department of Genome Integrity Institute of Molecular Genetics v v i Academy of Sciences of the Czech Republic Prague Czech Republic

Department of Tumour Immunology Institute of Molecular Genetics v v i Academy of Sciences of the Czech Republic Prague Czech Republic

Genome Integrity Unit Danish Cancer Society Research Center Copenhagen Denmark

See more in PubMed

J Cell Physiol. 2007 Jan;210(1):192-200 PubMed

Free Radic Biol Med. 2012 Oct 1;53(7):1489-99 PubMed

Circulation. 2003 Nov 4;108(18):2264-9 PubMed

Genes Cells. 2013 Jan;18(1):32-41 PubMed

FEBS Lett. 2012 Jul 4;586(14):1871-84 PubMed

Annu Rev Pathol. 2010;5:99-118 PubMed

Nat Cell Biol. 2013 Aug;15(8):978-90 PubMed

Free Radic Res. 2012 Jan;46(1):21-9 PubMed

Cancer Microenviron. 2012 Apr;5(1):39-44 PubMed

Biochem Biophys Res Commun. 2011 Aug 5;411(3):648-53 PubMed

Exp Cell Res. 1999 May 1;248(2):583-8 PubMed

Nature. 2005 Apr 14;434(7035):864-70 PubMed

Am J Physiol Lung Cell Mol Physiol. 2011 Feb;300(2):L295-304 PubMed

Cell Mol Life Sci. 2012 Jul;69(14):2327-43 PubMed

Cell Signal. 2014 Dec;26(12):2903-11 PubMed

Science. 1993 Sep 24;261(5129):1744-6 PubMed

Free Radic Biol Med. 2013 Apr;57:176-87 PubMed

Free Radic Biol Med. 2012 Nov 15;53(10):1903-18 PubMed

PLoS Biol. 2008 Dec 2;6(12):2853-68 PubMed

Proc Natl Acad Sci U S A. 1995 May 9;92(10):4337-41 PubMed

Cancer Res. 2009 Oct 1;69(19):7595-602 PubMed

Am J Physiol Lung Cell Mol Physiol. 2006 Apr;290(4):L661-L673 PubMed

FASEB J. 2007 Feb;21(2):356-65 PubMed

Methods. 2001 Dec;25(4):402-8 PubMed

Mol Biol Cell. 2006 Apr;17(4):1583-92 PubMed

Biochem J. 2008 May 15;412(1):123-30 PubMed

Nature. 1999 Feb 25;397(6721):710-3 PubMed

Biochem Biophys Res Commun. 1999 Feb 5;255(1):110-5 PubMed

Biochem J. 2013 Jun 1;452(2):231-9 PubMed

Nat Rev Cancer. 2003 Nov;3(11):807-21 PubMed

Physiol Rev. 2007 Jan;87(1):245-313 PubMed

Dev Biol. 1995 Mar;168(1):47-61 PubMed

Science. 1990 Sep 28;249(4976):1570-4 PubMed

Biochem J. 2002 Sep 1;366(Pt 2):613-21 PubMed

Oncogene. 2013 Apr 11;32(15):1971-7 PubMed

Mol Cells. 2011 Jul;32(1):99-106 PubMed

Biochem Biophys Res Commun. 2010 Jun 11;396(4):901-7 PubMed

Nature. 2005 Aug 4;436(7051):642 PubMed

J Biol Chem. 2012 Aug 3;287(32):26702-14 PubMed

Oncogene. 2010 Jan 14;29(2):273-84 PubMed

Anticancer Res. 2013 Oct;33(10):4431-8 PubMed

Science. 2008 Mar 7;319(5868):1352-5 PubMed

Cell. 2008 Jun 13;133(6):1006-18 PubMed

Exp Cell Res. 1995 Sep;220(1):186-93 PubMed

Nature. 2003 Oct 9;425(6958):577-84 PubMed

Oncogene. 2008 Aug 21;27(36):4921-32 PubMed

Mech Ageing Dev. 2009 Mar;130(3):179-88 PubMed

J Biol Chem. 2001 Jan 26;276(4):2531-7 PubMed

J Biol Chem. 1998 Mar 6;273(10):5858-68 PubMed

Proc Natl Acad Sci U S A. 2012 Dec 11;109(50):20596-601 PubMed

Nat Cell Biol. 2009 Aug;11(8):973-9 PubMed

PLoS One. 2010 Feb 12;5(2):e9188 PubMed

FEBS J. 2010 Jul;277(13):2853-67 PubMed

PLoS One. 2012;7(5):e36909 PubMed

Biochem J. 2009 Oct 12;423(3):363-74 PubMed

Nature. 2005 Aug 4;436(7051):660-5 PubMed

Biosci Biotechnol Biochem. 2003 Apr;67(4):815-21 PubMed

J Biol Chem. 2003 Aug 15;278(33):30624-33 PubMed

Cancer Biol Ther. 2008 Jun;7(6):864-72 PubMed

Free Radic Biol Med. 2008 Feb 1;44(3):332-42 PubMed

Nat Rev Mol Cell Biol. 2014 Jul;15(7):482-96 PubMed

Nature. 2013 Feb 21;494(7437):361-5 PubMed

Genes Dev. 2000 Jan 15;14(2):163-76 PubMed

Nature. 2011 Nov 09;479(7374):547-51 PubMed

Aging Cell. 2012 Apr;11(2):345-9 PubMed

Am J Physiol Renal Physiol. 2005 Oct;289(4):F816-25 PubMed

Oncogene. 2000 Mar 23;19(13):1698-709 PubMed

Cell. 2008 Jun 13;133(6):1019-31 PubMed

Nature. 2007 Feb 8;445(7128):656-60 PubMed

Nature. 2005 Aug 4;436(7051):725-30 PubMed

Mutagenesis. 2012 Nov;27(6):673-81 PubMed

Cell Death Differ. 2014 Jun;21(6):998-1012 PubMed

Cancer Metastasis Rev. 2010 Jun;29(2):273-83 PubMed

Nat Cell Biol. 2008 Aug;10(8):887-9 PubMed

Oncogene. 2001 Apr 26;20(18):2264-72 PubMed

Ann N Y Acad Sci. 2002 Nov;973:44-8 PubMed

J Cell Biol. 2000 Dec 25;151(7):1381-90 PubMed

Aging (Albany NY). 2012 Dec;4(12):932-51 PubMed

J Hepatol. 2008 Dec;49(6):965-76 PubMed

PLoS Biol. 2010 Sep 07;8(9):null PubMed

Nature. 2011 Nov 02;479(7372):232-6 PubMed

Nature. 2006 Nov 30;444(7119):638-42 PubMed

Cardiovasc Res. 2006 Jul 15;71(2):289-99 PubMed

Blood. 2007 Feb 15;109 (4):1373-80 PubMed

J Biol Chem. 2006 Oct 6;281(40):29568-74 PubMed

Arterioscler Thromb Vasc Biol. 2010 Jan;30(1):105-12 PubMed

Cell. 2008 Aug 22;134(4):657-67 PubMed

Cell Death Differ. 2013 Nov;20(11):1485-97 PubMed

Oncogene. 1995 Dec 21;11(12 ):2565-73 PubMed

Cell Cycle. 2013 Oct 1;12(19):3146-53 PubMed

Oncogene. 2012 Mar 1;31(9):1117-29 PubMed

Ann N Y Acad Sci. 1989;557:192-8, discussion 198-9 PubMed

Cancer Cell. 2012 Apr 17;21(4):517-31 PubMed

J Interferon Cytokine Res. 2002 Nov;22(11):1089-98 PubMed

Exp Mol Pathol. 2001 Feb;70(1):43-53 PubMed

Nature. 2005 Aug 4;436(7051):720-4 PubMed

Nature. 2006 Nov 30;444(7119):633-7 PubMed

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