Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

The PLA2R1-JAK2 pathway upregulates ERRα and its mitochondrial program to exert tumor-suppressive action

Oncogene volume 35, pages 5033–5042 (2016)Cite this article

Subjects

Abstract

Little is known about the biological role of the phospholipase A2 receptor (PLA2R1) transmembrane protein. In recent years, PLA2R1 has been shown to have an important role in regulating tumor-suppressive responses via JAK2 activation, but the underlying mechanisms are largely undeciphered. In this study, we observed that PLA2R1 increases the mitochondrial content, judged by increased levels of numerous mitochondrial proteins, of the mitochondrial structural component cardiolipin, of the mitochondrial DNA content, and of the mitochondrial DNA replication and transcription factor TFAM. This effect of PLA2R1 relies on a transcriptional program controlled by the estrogen-related receptor alpha1 (ERRα) mitochondrial master regulator. Expression of ERRα and of its nucleus-encoded mitochondrial targets is upregulated upon PLA2R1 ectopic expression, and this effect is mediated by JAK2. Conversely, downregulation of PLA2R1 decreases the level of ERRα and of its nucleus-encoded mitochondrial targets. Finally, blocking the ERRα-controlled mitochondrial program largely inhibits the PLA2R1-induced tumor-suppressive response. Together, our data document ERRα and its mitochondrial program as downstream effectors of the PLA2R1-JAK2 pathway leading to oncosuppression.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Augert A, Payre C, de Launoit Y, Gil J, Lambeau G, Bernard D . The M-type receptor PLA2R regulates senescence through the p53 pathway. EMBO Rep 2009; 10: 271–277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Vindrieux D, Augert A, Girard CA, Gitenay D, Lallet-Daher H, Wiel C et al. PLA2R1 mediates tumor suppression by activating JAK2. Cancer Res 2013; 73: 6334–6345.

    Article  CAS  PubMed  Google Scholar 

  3. Augert A, Vindrieux D, Girard CA, Le Calvé B, Gras B, Ferrand M et al. PLA2R1 kills cancer cells by inducing mitochondrial stress. Free Radic Biol Med 2013; 65C: 969–977.

    Article  Google Scholar 

  4. Vindrieux D, Devailly G, Augert A, Le CB, ferrand M, Pigny P et al. Repression of PLA2R1 by c-MYC and HIF-2alpha promotes cancer growth. Oncotarget 2014; 5: 1004–1013.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bernard D, Vindrieux D . PLA2R1: expression and function in cancer. Biochim Biophys Acta 2014; 1846: 40–44.

    CAS  PubMed  Google Scholar 

  6. Menschikowski M, Platzbecker U, Hagelgans A, Vogel M, Thiede C, Schonefeldt C et al. Aberrant methylation of the M-type phospholipase A(2) receptor gene in leukemic cells. BMC Cancer 2012; 12: 576.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sonoda J, Laganiere J, Mehl IR, Barish GD, Chong LW, Li X et al. Nuclear receptor ERR alpha and coactivator PGC-1 beta are effectors of IFN-gamma-induced host defense. Genes Dev 2007; 21: 1909–1920.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Villena JA, Hock MB, Chang WY, Barcas JE, Giguere V, Kralli A . Orphan nuclear receptor estrogen-related receptor alpha is essential for adaptive thermogenesis. Proc Natl Acad Sci USA 2007; 104: 1418–1423.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Schreiber SN, Emter R, Hock MB, Knutti D, Cardenas J, Podvinec M et al. The estrogen-related receptor alpha (ERRalpha) functions in PPARgamma coactivator 1alpha (PGC-1alpha)-induced mitochondrial biogenesis. Proc Natl Acad Sci USA 2004; 101: 6472–6477.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Starr R, Willson TA, Viney EM, Murray LJ, Rayner JR, Jenkins BJ et al. A family of cytokine-inducible inhibitors of signalling. Nature 1997; 387: 917–921.

    Article  CAS  PubMed  Google Scholar 

  11. Schindler C, Darnell JE Jr . Transcriptional responses to polypeptide ligands: the JAK-STAT pathway. Annu Rev Biochem 1995; 64: 621–651.

    Article  CAS  PubMed  Google Scholar 

  12. Schindler C, Levy DE, Decker T . JAK-STAT signaling: from interferons to cytokines. J Biol Chem 2007; 282: 20059–20063.

    Article  CAS  PubMed  Google Scholar 

  13. Willy PJ, Murray IR, Qian J, Busch BB, Stevens Jr WC, Martin R et al. Regulation of PPARgamma coactivator 1alpha (PGC-1alpha) signaling by an estrogen-related receptor alpha (ERRalpha) ligand. Proc Natl Acad Sci USA 2004; 101: 8912–8917.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bianco S, Sailland J, Vanacker JM . ERRs and cancers: effects on metabolism and on proliferation and migration capacities. J Steroid Biochem Mol Biol 2012; 130: 180–185.

    Article  CAS  PubMed  Google Scholar 

  15. Deblois G, Giguere V . Oestrogen-related receptors in breast cancer: control of cellular metabolism and beyond. Nat Rev Cancer 2013; 13: 27–36.

    Article  CAS  PubMed  Google Scholar 

  16. Miwa S, Jow H, Baty K, Johnson A, Czapiewski R, Saretzki G et al. Low abundance of the matrix arm of complex I in mitochondria predicts longevity in mice. Nat Commun 2014; 5: 3837.

    Article  CAS  PubMed  Google Scholar 

  17. Deblois G, Chahrour G, Perry MC, Sylvain-Drolet G, Muller WJ, Giguere V . Transcriptional control of the ERBB2 amplicon by ERRalpha and PGC-1beta promotes mammary gland tumorigenesis. Cancer Res 2010; 70: 10277–10287.

    Article  CAS  PubMed  Google Scholar 

  18. Fradet A, Sorel H, Bouazza L, Goehrig D, Depalle B, Bellahcene A et al. Dual function of ERRalpha in breast cancer and bone metastasis formation: implication of VEGF and osteoprotegerin. Cancer Res 2011; 71: 5728–5738.

    Article  CAS  PubMed  Google Scholar 

  19. Sailland J, Tribollet V, Forcet C, Billon C, Barenton B, Carnesecchi J et al. Estrogen-related receptor alpha decreases RHOA stability to induce orientated cell migration. Proc Natl Acad Sci USA 2014; 111: 15108–15113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hong EJ, Levasseur MP, Dufour CR, Perry MC, Giguere V . Loss of estrogen-related receptor alpha promotes hepatocarcinogenesis development via metabolic and inflammatory disturbances. Proc Natl Acad Sci USA 2013; 110: 17975–17980.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ao A, Wang H, Kamarajugadda S, Lu J . Involvement of estrogen-related receptors in transcriptional response to hypoxia and growth of solid tumors. Proc Natl Acad Sci USA 2008; 105: 7821–7826.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Arany Z, Foo SY, Ma Y, Ruas JL, Bommi-Reddy A, Girnun G et al. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha. Nature 2008; 451: 1008–1012.

    Article  CAS  PubMed  Google Scholar 

  23. Zou C, Yu S, Xu Z, Wu D, Ng CF, Yao X et al. ERRalpha augments HIF-1 signalling by directly interacting with HIF-1alpha in normoxic and hypoxic prostate cancer cells. J Pathol 2014; 233: 61–73.

    Article  CAS  PubMed  Google Scholar 

  24. Li Y, Padmanabha D, Gentile LB, Dumur CI, Beckstead RB, Baker KD . HIF- and non-HIF-regulated hypoxic responses require the estrogen-related receptor in Drosophila melanogaster. PLoS Genet 2013; 9: e1003230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ferbeyre G, Moriggl R . The role of Stat5 transcription factors as tumor suppressors or oncogenes. Biochim Biophys Acta 2011; 1815: 104–114.

    CAS  PubMed  Google Scholar 

  26. Manna S, Bostner J, Sun Y, Miller LD, Alayev A, Schwarts NS et al. ERRalpha is a marker of tamoxifen response and survival in triple-negative breast cancer. Clin Cancer Res 2015, e-pub ahead of print 5 November 2015.

  27. Sasaki A, Inagaki-Ohara K, Yoshida T, Yamanaka A, Sasaki M, Yasukawa H et al. The N-terminal truncated isoform of SOCS3 translated from an alternative initiation AUG codon under stress conditions is stable due to the lack of a major ubiquitination site, Lys-6. J Biol Chem 2003; 278: 2432–2436.

    Article  CAS  PubMed  Google Scholar 

  28. Gallet M, Saidi S, Hay E, Photsavang J, Marty C, Sailland J et al. Repression of osteoblast maturation by ERRalpha accounts for bone loss induced by estrogen deficiency. PLoS One 2013; 8: e54837.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Devailly G, Grandin M, Perriaud L, Mathot P, Delcros JG, Bidet Y et al. Dynamics of MBD2 deposition across methylated DNA regions during malignant transformation of human mammary epithelial cells. Nucleic Acids Res 2015; 43: 5838–5854.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the laboratory members for helpful discussions. This work was carried out with the support of the Association for International Cancer Research (AICR-11-0722) and the ANR (ANR-14-CE12-0003) for DB, the Groupe Pasteur Mutualité for LE and the Ligue contre le cancer, comité du Puy de Dome et de la Drome for JMV.

Author information

Author notes

  1. D Vindrieux and D Bernard: These authors contributed equally to this work.

Authors and Affiliations

  1. Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France

    A Griveau, G Devailly, L Eberst, B Le Calvé, M Ferrand, A Augert, R Dante, D Vindrieux & D Bernard

  2. CNRS UMR 5286, Lyon, France

    A Griveau, G Devailly, L Eberst, B Le Calvé, M Ferrand, A Augert, R Dante, D Vindrieux & D Bernard

  3. Centre Léon Bérard, Lyon, France

    A Griveau, G Devailly, L Eberst, B Le Calvé, M Ferrand, A Augert, R Dante, D Vindrieux & D Bernard

  4. Université de Lyon, Lyon, France

    A Griveau, G Devailly, L Eberst, B Le Calvé, M Ferrand, A Augert, R Dante, D Vindrieux & D Bernard

  5. Cellular Stress Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Campus, London, UK

    N Navaratnam

  6. Biological Mass Spectrometry and Proteomics Laboratory, MRC Clinical Sciences Centre, Imperial College London, London, UK

    P Faull

  7. Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon I, CNRS UMR5242, Ecole Normale Supérieure de Lyon, Lyon, France

    J M Vanacker

Authors
  1. A Griveau
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G Devailly
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L Eberst
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N Navaratnam
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B Le Calvé
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Ferrand
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. P Faull
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A Augert
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. R Dante
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J M Vanacker
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. D Vindrieux
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. D Bernard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D Bernard.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Griveau, A., Devailly, G., Eberst, L. et al. The PLA2R1-JAK2 pathway upregulates ERRα and its mitochondrial program to exert tumor-suppressive action. Oncogene 35, 5033–5042 (2016). https://doi.org/10.1038/onc.2016.43

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2016.43

This article is cited by

Search

Advanced search

Quick links