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:

PTPN12 promotes resistance to oxidative stress and supports tumorigenesis by regulating FOXO signaling

Oncogene volume 33, pages 1047–1054 (2014)Cite this article

Subjects

Abstract

It is well known that protein tyrosine phosphatases (PTPs) that become oxidized due to exposure to reactive oxygen species (ROS) undergo a conformational change and are inactivated. However, whether PTPs can actively regulate ROS levels in order to prevent PTP inhibition has yet to be investigated. Here, we demonstrate that PTP non-receptor type 12 (PTPN12) protects cells against aberrant ROS accumulation and death induced by oxidative stress. Murine embryonic fibroblasts (MEFs) deficient in PTPN12 underwent increased ROS-induced apoptosis under conditions of antioxidant depletion. Cells lacking PTPN12 also showed defective activation of FOXO1/3a, transcription factors required for the upregulation of several antioxidant genes. PTPN12-mediated regulation of ROS appeared to be mediated by phosphoinositide-dependent kinase-1 (PDK1), which was hyperstimulated in the absence of PTPN12. As tight regulation of ROS to sustain survival is a key feature of cancer cells, we examined PTPN12 levels in tumors from a cohort of breast cancer patients. Patients whose tumors showed high levels of PTPN12 transcripts had a significantly poorer prognosis. Analysis of tissues from patients with various breast cancer subtypes revealed that more triple-negative breast cancers, the most aggressive breast cancer subtype, showed high PTPN12 expression than any other subtype. Furthermore, both human breast cancer cells and mouse mammary epithelial tumor cells engineered to lack PTPN12 exhibited reduced tumorigenic and metastatic potential in vivo that correlated with their elevated ROS levels. The involvement of PTPN12 in the antioxidant response of breast cancer cells suggests that PTPN12 may represent a novel therapeutic target for this disease.

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
Figure 6

Similar content being viewed by others

References

  1. Xu D, Rovira II, Finkel T . Oxidants painting the cysteine chapel: redox regulation of PTPs. Dev Cell 2002; 2: 251–252.

    Article  CAS  Google Scholar 

  2. Karisch R, Fernandez M, Taylor P, Virtanen C, St-Germain JR, Jin LL et al. Global proteomic assessment of the classical protein-tyrosine phosphatome and ‘redoxome’. Cell 2011; 146: 826–840.

    Article  CAS  Google Scholar 

  3. Wiseman H, Halliwell B . Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer. Biochem J 1996; 313: 17–29.

    Article  CAS  Google Scholar 

  4. Schafer ZT, Grassian AR, Song L, Jiang Z, Gerhart-Hines Z, Irie HY et al. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 2009; 461: 109–113.

    Article  CAS  Google Scholar 

  5. Storz P . Forkhead homeobox type O transcription factors in the responses to oxidative stress. Antioxid Redox Signal 2011; 14: 593–605.

    Article  CAS  Google Scholar 

  6. Greer EL, Brunet A . FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 2005; 24: 7410–7425.

    Article  CAS  Google Scholar 

  7. Myatt SS, Brosens JJ, Lam EW . Sense and sensitivity: FOXO and ROS in cancer development and treatment. Antioxid Redox Signal 2011; 14: 675–687.

    Article  CAS  Google Scholar 

  8. Cote JF, Charest A, Wagner J, Tremblay ML . Combination of gene targeting and substrate trapping to identify substrates of protein tyrosine phosphatases using PTP-PEST as a model. Biochemistry 1998; 37: 13128–13137.

    Article  CAS  Google Scholar 

  9. Cairns RA, Harris IS, Mak TW . Regulation of cancer cell metabolism. Nat Rev Cancer 2011; 11: 85–95.

    Article  CAS  Google Scholar 

  10. Vaughn AE, Deshmukh M . Glucose metabolism inhibits apoptosis in neurons and cancer cells by redox inactivation of cytochrome c. Nat Cell Biol 2008; 10: 1477–1483.

    Article  CAS  Google Scholar 

  11. Meister A . Selective modification of glutathione metabolism. Science 1983; 220: 472–477.

    Article  CAS  Google Scholar 

  12. DeBerardinis RJ, Cheng T . Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 2010; 29: 313–324.

    Article  CAS  Google Scholar 

  13. Barr AJ, Ugochukwu E, Lee WH, King ON, Filippakopoulos P, Alfano I et al. Large-scale structural analysis of the classical human protein tyrosine phosphatome. Cell 2009; 136: 352–363.

    Article  CAS  Google Scholar 

  14. Nogueira V, Park Y, Chen CC, Xu PZ, Chen ML, Tonic I et al. Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Cancer Cell 2008; 14: 458–470.

    Article  CAS  Google Scholar 

  15. Casamayor A, Morrice NA, Alessi DR . Phosphorylation of Ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1: identification of five sites of phosphorylation in vivo. Biochem J 1999; 342 (Pt 2): 287–292.

    Article  CAS  Google Scholar 

  16. Yang KJ, Shin S, Piao L, Shin E, Li Y, Park KA et al. Regulation of 3-phosphoinositide-dependent protein kinase-1 (PDK1) by Src involves tyrosine phosphorylation of PDK1 and Src homology 2 domain binding. J Biol Chem 2008; 283: 1480–1491.

    Article  CAS  Google Scholar 

  17. Brunet A, Park J, Tran H, Hu LS, Hemmings BA, Greenberg ME . Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol Cell Biol 2001; 21: 952–965.

    Article  CAS  Google Scholar 

  18. Park J, Leong ML, Buse P, Maiyar AC, Firestone GL, Hemmings BA . Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3-kinase-stimulated signaling pathway. EMBO J 1999; 18: 3024–3033.

    Article  CAS  Google Scholar 

  19. Rogoff D, Black K, McMillan DR, White PC . Contribution of hexose-6-phosphate dehydrogenase to NADPH content and redox environment in the endoplasmic reticulum. Redox Rep 2010; 15: 64–70.

    Article  CAS  Google Scholar 

  20. Ishimoto T, Nagano O, Yae T, Tamada M, Motohara T, Oshima H et al. CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc(-) and thereby promotes tumor growth. Cancer Cell 2011; 19: 387–400.

    Article  CAS  Google Scholar 

  21. Cheng Z, Guo S, Copps K, Dong X, Kollipara R, Rodgers JT et al. Foxo1 integrates insulin signaling with mitochondrial function in the liver. Nat Med 2009; 15: 1307–1311.

    Article  CAS  Google Scholar 

  22. Nemoto S, Finkel T . Redox regulation of forkhead proteins through a p66shc-dependent signaling pathway. Science 2002; 295: 2450–2452.

    Article  CAS  Google Scholar 

  23. Essafi A, Fernandez de Mattos S, Hassen YA, Soeiro I, Mufti GJ, Thomas NS et al. Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells. Oncogene 2005; 24: 2317–2329.

    Article  CAS  Google Scholar 

  24. Streit S, Ruhe JE, Knyazev P, Knyazeva T, Iacobelli S, Peter S et al. PTP-PEST phosphatase variations in human cancer. Cancer Genet Cytogenet 2006; 170: 48–53.

    Article  CAS  Google Scholar 

  25. Chin K, DeVries S, Fridlyand J, Spellman PT, Roydasgupta R, Kuo WL et al. Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell 2006; 10: 529–541.

    Article  CAS  Google Scholar 

  26. Hoadley KA, Weigman VJ, Fan C, Sawyer LR, He X, Troester MA et al. EGFR associated expression profiles vary with breast tumor subtype. BMC Genomics 2007; 8: 258.

    Article  Google Scholar 

  27. Cheang MC, Voduc D, Bajdik C, Leung S, McKinney S, Chia SK et al. Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res 2008; 14: 1368–1376.

    Article  CAS  Google Scholar 

  28. Arpaia E, Blaser H, Quintela-Fandino M, Duncan G, Leong HS, Ablack A et al. The interaction between caveolin-1 and Rho-GTPases promotes metastasis by controlling the expression of alpha5-integrin and the activation of Src, Ras and Erk. Oncogene 2011; 31: 884–896.

    Article  Google Scholar 

  29. Forteleoni G, Argiolas L, Farris A, Ferraris AM, Gaetani GF, Meloni T . G6PD deficiency and breast cancer. Tumori 1988; 74: 665–667.

    Article  CAS  Google Scholar 

  30. Bailey HH, Ripple G, Tutsch KD, Arzoomanian RZ, Alberti D, Feierabend C et al. Phase I study of continuous-infusion L-S,R-buthionine sulfoximine with intravenous melphalan. J Natl Cancer Inst 1997; 89: 1789–1796.

    Article  CAS  Google Scholar 

  31. Sun T, Aceto N, Meerbrey KL, Kessler JD, Zhou C, Migliaccio I et al. Activation of multiple proto-oncogenic tyrosine kinases in breast cancer via loss of the PTPN12 phosphatase. Cell 2011; 144: 703–718.

    Article  CAS  Google Scholar 

  32. Bakker WJ, Harris IS, Mak TW . FOXO3a is activated in response to hypoxic stress and inhibits HIF1-induced apoptosis via regulation of CITED2. Mol Cell 2007; 28: 941–953.

    Article  CAS  Google Scholar 

  33. Allred DC, Harvey JM, Berardo M, Clark GM . Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol 1998; 11: 155–168.

    CAS  PubMed  Google Scholar 

  34. Yerushalmi R, Gelmon KA, Leung S, Gao D, Cheang M, Pollak M et al. Insulin-like growth factor receptor (IGF-1R) in breast cancer subtypes. Breast Cancer Res Treat 2011; 132: 131–142.

    Article  Google Scholar 

Download references

Acknowledgements

We thank Dr Anne Brüstle and Dr Dirk Brenner for helpful discussions, Dr Han You and Dr Walbert Bakker for reagents and Dr Mary Saunders for insightful scientific editing. This work was supported by a PGS-D grant from the Natural Sciences and Engineering Council of Canada (ISH) and grant no. 179815 from the Canadian Institutes of Health Research (TWM).

Author information

Authors and Affiliations

  1. The Campbell Family Institute for Breast Cancer Research at Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada

    I S Harris, H Blaser, J Moreno, A E Treloar, C Gorrini, M Sasaki, J M Mason, C B Knobbe, A J Elia, A Wakeham, S Done & T W Mak

  2. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    I S Harris, S Done & T W Mak

  3. Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada

    J Moreno & S Done

  4. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

    J Moreno & S Done

  5. Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany

    C B Knobbe

  6. Laboratory of Apoptosis in Cancer, MRC Toxicology Unit, University of Leicester, Leicester, UK

    A Rufini & G Melino

  7. Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec, Canada

    M Hallé & M L Tremblay

Authors
  1. I S Harris
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H Blaser
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Moreno
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A E Treloar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C Gorrini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Sasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J M Mason
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C B Knobbe
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A Rufini
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M Hallé
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. A J Elia
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. A Wakeham
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. M L Tremblay
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. G Melino
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. S Done
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. T W Mak
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T W Mak.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Harris, I., Blaser, H., Moreno, J. et al. PTPN12 promotes resistance to oxidative stress and supports tumorigenesis by regulating FOXO signaling. Oncogene 33, 1047–1054 (2014). https://doi.org/10.1038/onc.2013.24

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2013.24

Keywords

This article is cited by

Search

Advanced search

Quick links