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Multidrug resistance protein 3 loss promotes tumor formation by inducing senescence escape

Oncogene volume 35, pages 1596–1601 (2016)Cite this article

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Abstract

Oncogenic-stress-induced senescence (OIS) is a stress response allowing normal cells, when receiving oncogenic signals, to stably arrest their proliferation. OIS thus acts to prevent aberrant cell proliferation and tumor formation. To identify novel tumor suppressive pathways, we have recently completed a loss-of-function genetic screen to identify novel genes promoting escape from OIS and thus, potentially, tumor formation when their functions are lost. Using this approach, we unexpectedly found that loss of function of the multidrug resistance protein 3 (MRP3 or ABCC3) promotes escape from OIS in human epithelial cells. Importantly, ABCC3 expression is reduced in human skin tumors, and ABCC3-knockout mice display increased sensitivity to RAS-induced skin carcinogenesis, concomitantly with decreased OIS. ABCC3 participates in resistance to chemotherapy via its transporter activity. Our data show that this transporter activity is involved in ABCC3-induced senescence, demonstrating that this protein has a complex role in cancer, since its loss of function may promote escape from OIS and tumor formation whereas its gain of function promotes resistance to chemotherapy.

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Acknowledgements

We thank Léa Payen for advice and Sarah Kabani for critical reading of the manuscript. This work was carried out with the support of the French National Cancer Institute (grants plbio 2010-181), the ‘Ligue contre le Cancer, comité de la Savoie’, the ‘Fondation ARC’, and the ‘RTRS Fondation Synergie Lyon Cancer’. CW is supported by the ‘Ligue Nationale contre le Cancer’ and the ‘Fondation pour la Recherche Médicale’.

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Author notes

  1. C Wiel, B Gras, D Vindrieux and M Warnier: These authors contributed equally to this work.

Authors and Affiliations

  1. Tumoral Escape Department, Senescence Escape Mechanisms Laboratory, Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France

    C Wiel, B Gras, D Vindrieux, M Warnier, D Gitenay, B Le Calvé, M Ferrand, A Augert & D Bernard

  2. CNRS UMR5286, Lyon, France

    C Wiel, B Gras, D Vindrieux, M Warnier, D Gitenay, B Le Calvé, M Ferrand, A Augert & D Bernard

  3. Centre Léon Bérard, Lyon, France

    C Wiel, B Gras, D Vindrieux, M Warnier, D Gitenay, B Le Calvé, M Ferrand, A Augert & D Bernard

  4. Université de Lyon, Lyon, France

    C Wiel, B Gras, D Vindrieux, M Warnier, D Gitenay, B Le Calvé, M Ferrand, A Augert & D Bernard

Authors
  1. C Wiel
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  2. B Gras
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  3. D Vindrieux
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  5. D Gitenay
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  6. B Le Calvé
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  7. M Ferrand
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  8. A Augert
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  9. D Bernard
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Corresponding author

Correspondence to D Bernard.

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Supplementary Information accompanies this paper on the Oncogene website

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Wiel, C., Gras, B., Vindrieux, D. et al. Multidrug resistance protein 3 loss promotes tumor formation by inducing senescence escape. Oncogene 35, 1596–1601 (2016). https://doi.org/10.1038/onc.2015.218

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  • DOI: https://doi.org/10.1038/onc.2015.218

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