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Peroxiredoxin 2 specifically regulates the oxidative and metabolic stress response of human metastatic breast cancer cells in lungs

Oncogene volume 32, pages 724–735 (2013)Cite this article

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A Corrigendum to this article was published on 07 February 2013

Abstract

Little is known about metastatic pathways that are specific to the lung rather than other organs. We previously showed that antioxidant proteins such as peroxiredoxins were specifically upregulated in lung metastatic breast cancer cells. We hypothesize that cancer cells that live under aerobic conditions, as might be the case in lungs, protect themselves against the damage caused by reactive oxygen species (ROS). To examine this hypothesis, we studied the role of peroxiredoxin-2 (PRDX2) in lung vs bone metastasis formation. A metastatic variant of MDA-MB-435 breast cancer cells that specifically metastasize to lungs (435-L3) was transduced with short hairpin RNAs to specifically silence PRDX2. Conversely, a bone metastatic variant of MDA-MB-231 cells (BO2) was stably transfected to overexpress PRDX2. The 435-L3 cells silenced for PRDX2 were significantly more sensitive to H2O2-induced oxidative stress than the parental and scrambled transfected cells. BO2/PRDX2 cells produced less ROS than BO2/green fluorescent protein control cells under oxidative stress. Moreover, PRDX2 knockdown inhibited the growth of 435-L3 cells in the lungs, whereas lymph node metastasis remained unaffected. In contrast, PRDX2 overexpression in bone metastatic BO2 breast cancer cells led to drastic inhibition of the skeletal tumor burden and reduction of bone destruction. Furthermore, PRDX2 expression in breast cancer cells was associated with a glucose-dependent phenotype, different from bone metastatic cells. Overall, our results strongly suggest that PRDX2 is a targetable ‘metabolic adaptor’ driver protein implicated in the selective growth of metastatic cells in the lungs by protecting them against oxidative stress.

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Acknowledgements

We would like to thank Oriol Casanovas (Angiogenesis Laboratory, IDIBELL) for scientific discussions and his expert advice on angiogenesis. We would also like to thank Berta Martín, Vanessa Hernández and Dídac Dominguez for his expert technical assistance. We are grateful to Mr R Rycroft for expert language advice and Victor Moreno for expert statistical advice (Barcelona University). We thanks Jose Carlos Perales and Andy Méndez for the advice and support the metabolic analysis (Barcelona University). We acknowledge all the partners of the MetaBre consortium for their collaboration and stimulating criticism. This study was supported by grants from the Spanish Ministry of Health and Consumer Affairs (FIS/PI071245 and FIS/PI10/00057), EC MetaBre (contract no. LSHC-CT-2004-506049), INCA (ONCOIMAGE, n°07/3D1316/PF-108-01/NG-LC), the Ministry of Education and Science (SAF2004-0188-E), AECC Scientific Foundation and Private Foundation Cellex Barcelona.

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  1. V Stresing and E Baltziskueta: These authors contributed equally to the paper

Authors and Affiliations

  1. Biological Clues of the Invasive and Metastatic Phenotype Group, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain

    V Stresing, E Baltziskueta, MaC Arriba, C Nieva & A Sierra

  2. INSERM, UMR 664, IFR62, Laennec School of Medicine, Lyon, France

    V Stresing & P Clézardin

  3. Cardiovascular Research Center (CSIC-ICCC), CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

    N Rubio & J Blanco

  4. Institut de Recerca Biomèdica de Lleida (IRBLLEIDA), Lleida, Spain

    J Valls

  5. Servei d’Epidemiologia, IDIBELL-Institut Catala d’Oncologia, L’Hospitalet de Llobregat, Barcelona, Spain

    J Valls

  6. Edouard Herriot Hospital, Lyon, France

    M Janier

  7. Unit of Biomarkers and Susceptibility, and CIBERESP, IDIBELL-Institut Catala d’Oncologia, L’Hospitalet de Llobregat, Barcelona, Spain

    R Sanz-Pamplona

  8. ICFO-Institut de Ciències Fotòniques, Parc Mediterrani de Tecnologia, Castelldefels, E-Barcelona, Spain,

    M Marro & P Dmitri

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Stresing, V., Baltziskueta, E., Rubio, N. et al. Peroxiredoxin 2 specifically regulates the oxidative and metabolic stress response of human metastatic breast cancer cells in lungs. Oncogene 32, 724–735 (2013). https://doi.org/10.1038/onc.2012.93

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