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IFNγ induces oxidative stress, DNA damage and tumor cell senescence via TGFβ/SMAD signaling-dependent induction of Nox4 and suppression of ANT2

Oncogene volume 35, pages 1236–1249 (2016)Cite this article

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Abstract

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.

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Abbreviations

ANT2:

adenine nucleotide translocase 2

DDR:

DNA damage response

IFN:

interferon

IL:

interleukin

JAK:

Janus kinase

PML:

promyelocytic leukemia protein

ROS:

reactive oxygen species

SA-β-gal:

senescence-associated beta-galactosidase

STAT:

signal transducers and activators of transcription

TGFβ:

transforming growth factor-beta

TNFα:

tumor necrosis factor alpha.

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Acknowledgements

We thank Marketa Vancurova and Katerina Krejcikova for excellent technical assistance. This study was supported by the Grant Agency of the Czech Republic (Project 13-17658S), NT14461 grant from the Grant Agency of the Ministry of Health of the Czech Republic and Institutional Grant (Project RVO 68378050). SH was supported by Academy of Sciences of the Czech Republic (Project L200521301), LK was supported in part by the Faculty of Science, Charles University, Prague.

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Author notes

  1. G Michlits, M Reinis & O Korolov

    Present address: 4Present address: Laboratory of Immunology, Czech Centre for Phenogenomics, Institute of Molecular Genetics, v.v.i., AS CR, Prague, Czech Republic.,

Authors and Affiliations

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

    S Hubackova, A Kucerova, L Kyjacova, J Bartek & Z Hodny

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

    G Michlits, M Reinis & O Korolov

  3. Genome Integrity Unit, Danish Cancer Society Research Center, Copenhagen, Denmark

    J Bartek

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  3. G Michlits
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  4. L Kyjacova
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  7. J Bartek
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Correspondence to J Bartek or Z Hodny.

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Hubackova, S., Kucerova, A., Michlits, G. et al. IFNγ induces oxidative stress, DNA damage and tumor cell senescence via TGFβ/SMAD signaling-dependent induction of Nox4 and suppression of ANT2. Oncogene 35, 1236–1249 (2016). https://doi.org/10.1038/onc.2015.162

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