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:

c-Jun N-terminal kinase is activated in non-small-cell lung cancer and promotes neoplastic transformation in human bronchial epithelial cells

Oncogene volume 26, pages 2658–2666 (2007)Cite this article

Abstract

c-Jun N-terminal kinase (JNK) has been reported to either potentiate or inhibit oncogenesis, depending upon the cellular context, but its role in lung neoplasia is unclear. Here we sought to define the role of JNK in lung neoplasia by examining evidence of JNK phosphorylation in non-small-cell lung cancer (NSCLC) biopsy samples and by using genetic and pharmacologic approaches to modulate JNK expression and activity in cultured cells. Immunohistochemical staining for JNK phosphorylation was detected in 114 (45%) of 252 NSCLC biopsy samples and was predominantly nuclear, providing evidence of JNK activation in a subset of NSCLC cases. Introduction of a doxycycline-inducible, constitutively active, mutant mitogen-activated protein kinase kinase 4 (MKK4) into the human bronchial epithelial cell lines BEAS-2B and HB56B increased the cells’ proliferation, migration, invasion and clonogenicity. Depletion of JNK in MKK4 mutant-transformed BEAS-2B cells by introduction of JNK1/2 short hairpin RNA reversed the transformed phenotype, indicating that JNK activation is oncogenic and MKK4 confers neoplastic properties in these cells. The proliferation of NSCLC cell lines HCC827 and H2009, in which JNK and its substrate c-Jun are constitutively phosphorylated, was inhibited by SP600125, a JNK kinase inhibitor. We conclude that JNK is activated in a subset of NSCLC biopsy samples and promotes oncogenesis in the bronchial epithelium, suggesting that strategies to inhibit the JNK pathway should be considered for the prevention and treatment of NSCLC.

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

  • Bachmeier BE, VenĂ© R, Iancu CM, Pfeffer U, Mayer B, Noonan D et al. (2005). Transcriptional control of cell density dependent regulation of matrix metalloproteinase and TIMP expression in breast cancer cell lines. Thromb Haemost 293: 761–769.

    Google Scholar 

  • Bakiri L, Lallemand D, EWetzel EB, Yaniv M . (2000). Cell cycle-dependent variations in c-Jun and JunB phosphorylation: a role in the control of cyclin D1 expression. EMBO J 19: 2056–2068.

    Article  CAS  Google Scholar 

  • Belguise K, Kersual K, Galtier F, Chalbos D . (2005). FRA-1 expression level regulates proliferation and invasiveness of breast cancer cells. Oncogene 24: 1434–1444.

    Article  CAS  Google Scholar 

  • Bost F, McKay R, Bost M, Potapova O, Dean NM, Mercola D . (1999). The Jun N-terminal kinase 2 isoform is preferentially required for epidermal growth factor-induced transformation of human A549 lung adenocarcinoma cells. Mol Cell Biol 19: 1938–1949.

    Article  CAS  Google Scholar 

  • Briggs J, Chamboredon S, Castellazzi M, Kerry JA, Bos TJ . (2002). Transcriptional upregulation of SPARC, in response to c-Jun overexpression, contributes to increased motility and invasion of MCF7 breast cancer cells. Oncogene 21: 7077–7091.

    Article  CAS  Google Scholar 

  • Cazillis M, Bringuier AF, Delautier D, Buisine M, Bernuau D, Gespach C et al. (2004). Disruption of MKK4 signaling reveals its tumor-suppressor role in embryonic stem cells. Oncogene 23: 4735–4744.

    Article  CAS  Google Scholar 

  • Davies H, Hunter C, Smith R, Stephens P, Greenman C, Bignell G et al. (2005). Somatic mutations of the protein kinase gene family in human lung cancer. Cancer Res 65: 7591–7595.

    Article  CAS  Google Scholar 

  • Gallo TK, Johnson GL . (2002). Mixed-lineage kinase control of JNK and p38 MAPK pathways. Nat Rev Mol Cell Biol 3: 663–672.

    Article  CAS  Google Scholar 

  • Geqiang L, Xiang Y, Sabapathy K, Silverman RH . (2004). An apoptotic signaling pathway in the interferon antiviral response mediated by RNase L and cJun N-terminal kinase. J Biol Chem 279: 1123–1131.

    Article  Google Scholar 

  • Hess P, Pihan G, Sawyers CL, Flavell RA, Davis RJ . (2002). Survival signaling mediated by c-Jun N-terminal kinase in transformed B lymphoblasts. Nat Genet 32: 201–205.17.

    Article  CAS  Google Scholar 

  • Huang C, Jacobson K, Schaller MD . (2004). MAP Kinases and cell migration. J Cell Science 117: 4619–4628.

    Article  CAS  Google Scholar 

  • Huang C, Rajfur Z, Borchers C, Schaller MD, Jacobson K . (2003). JNK phosphorylates paxillin and regulates cell migration. Nature 424: 219–223.

    Article  CAS  Google Scholar 

  • Ip YT, Davis RJ . (1998). Signal transduction by the cJun N-terminal kinase (JNK) -from inflammation to development. Curr Opin Cell Biol 10: 205–219.

    Article  CAS  Google Scholar 

  • Kennedy NJ, Davis RJ . (2003). Role of JNK in tumor development. Cell Cycle 2: 199–201.

    CAS  PubMed  Google Scholar 

  • Kennedy NJ, Sluss HK, Jones SN, Bar-Sagi D, Flavell RA, Davis RJ . (2003). Suppression of Ras-stimulated transformation by the JNK signal transduction pathway. Genes Dev 17: 629–637.

    Article  CAS  Google Scholar 

  • Kim HL, Vander-Griend DJ, Yang X, Benson DA, Dubauskas Z, Yoshida BA et al. (2001). Mitogen-activated protein kinase kinase 4 metastasis suppressor gene expression is inversely related to histological pattern in advancing human prostatic cancers. Cancer Res 61: 2833–2837.

    CAS  PubMed  Google Scholar 

  • Kim MH, Yoo HS, Chang HJ, Hong MH, Kim HD, Chung IJ et al. (2005). Cell cycle-dependent variations in c-Jun and JunB phosphorylation: a role in the control of cyclin D1 expression. Biochem Biophys Res Commun 2333: 874–880.

    Article  Google Scholar 

  • Lee HY, Suh YA, Lee JI, Hassan KA, Mao L, Force T et al. (2002). Inhibition of oncogenic K-ras signaling by aerosolized gene delivery in a mouse model of human lung cancer. Clin Cancer Res 8: 2970–2975.

    CAS  PubMed  Google Scholar 

  • Lee HY, Suh YA, Xia D, Lu Y, Superty R, LaPushin R et al. (2003). Evidence that phosphatidylinositol 3-kinase- and mitogen-activated protein kinase kinase-4/c-Jun NH2-terminal kinase-dependent pathways cooperate to maintain lung cancer cell survival. J Biol Chem 278: 23630–23638.

    Article  CAS  Google Scholar 

  • Liu Y, Lu C, Shen Q, Medellin DM, Kim H, Brown PH . (2004). AP-1 blockade in breast cancer cells causes cell cycle arrest by suppressing G1 cyclin expression and reducing cyclin-dependent kinase activity. Oncogene 23: 8238–8246.18.

    Article  CAS  Google Scholar 

  • Lorusso PM, Adjei AA, Varterasian M, Gadgeel S, Reid J, Mitchell DY et al. (2005). Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol 23: 5281–5293.

    Article  CAS  Google Scholar 

  • Lu C, Shen Q, Dupre E, Kim H, Hilsenbeck S, Brown PH . (2005). c-Fos is critical for MCF breast cancer cell growth. Oncogene 24: 6516–6524.

    Article  CAS  Google Scholar 

  • Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW et al. (2004). Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350: 2129–2139.

    Article  CAS  Google Scholar 

  • Milde-langosch K, Roder H, Andritzky B, Aslan B, Hemminger G, Brinkmann A et al. (2004). The role of the AP-1 transcription factors c-Fos, FosB, Fra-1 and Fra-2 in the invasion process of mammary carcinomas. Breast Cancer Res Treat 86: 139–152.

    Article  CAS  Google Scholar 

  • Mitsudomi T, Viallet J, Mulshine JL, Linnoila I, Minna JD, Gazdar AF . (1991). Mutations of ras gene distinguish a subset of non-small-cell-lung cancer cell lines from small cell lung cancer cell lines. Oncogene 6: 1352–1362.

    Google Scholar 

  • Nishina H, Fischer KD, Radvanyi L, Shahinian A, Hakem R, Rubie EA et al. (1997). Stress-signalling kinase Sek1 protects thymocytes from apoptosis mediated by CD95 and CD3. Nature 385: 350–353.

    Article  CAS  Google Scholar 

  • Nishina H, Vaz C, Billia P, Nghiem M, Sasaki T, De la Pompa JL et al. (1999). Defective liver formation and liver cell apoptosis in mice lacking the stress signaling kinase SEK1/MKK4. Development 126: 505–516.

    CAS  PubMed  Google Scholar 

  • Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S et al. (2004). EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304: 1497–1500.

    Article  CAS  Google Scholar 

  • Parsons DW, Wang TL, Samuels Y, Bardelli A, Cummins JM, DeLong L et al. (2005). Colorectal cancer: mutations in a signalling pathway. Nature 436: 792.

    Article  CAS  Google Scholar 

  • Pollack JR, Perou CM, Alizadeh AA, Eisen MB, Pergamenschikov A, Williams CF et al. (1999). Genome wide analysis of DNA copy number changes using cDNA microarrays. Nat Genet 23: 41–46.

    Article  CAS  Google Scholar 

  • Pollack JR, Sorlie T, Perou CM, Rees CA, Jeffrey SS, Lonning PE et al. (2002). Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors. Proc Natl Acad Sci USA 99: 12963–12968.

    Article  CAS  Google Scholar 

  • Potapova O, Gorospe M, Bost F, Dean NM, Gaarde WA, Mercola D et al. (2000). c-Jun N-terminal kinase is essential for growth of human T98G glioblastoma cells. J Biol Chem 275: 24767–24775.

    Article  CAS  Google Scholar 

  • Potapova O, Haghigi A, Bost F, Liu C, Birrer MJ, Gjerset R et al. (1997). The Jun kinase/stress-activated protein kinase pathway functions to regulate DNA repair and inhibition of the pathway sensitizes tumor cells to cis-platin. J Biol Chem 272: 14041–14047.

    Article  CAS  Google Scholar 

  • Rangaswami H, Bulbule A, Kundu GC . (2005). JNK1 differentially regulates osteopontin-induced nuclear factor inducing kinase/MEKK1-dependent activating protein-1-mediated promatrix metalloproteinase-9 activation. J Biol Chem 280: 19381–19392.

    Article  CAS  Google Scholar 

  • Reddel RR, Hsu IC, Mass MJ, Hukku B, Gerwin BI, Salghetti SE et al. (1991). A human bronchial epithelial cell strain with unusual in vitro potential, which undergoes neoplastic transformation after SV40T antigen gene transfection. Int J Cancer 48: 764–773.

    Article  CAS  Google Scholar 

  • Reddel RR, Ke Y, Gerwin BI, McMenamin MG, Lechner JF, Su RT et al. (1988). Transformation of human bronchial epithelial cells by infection with SV40 or adenovirus-12 SV40 hybrid virus, or transfection via strontium phosphate co-precipitation with a plasmid containing SV40 early region genes. Cancer Res 48: 1904–1909.

    CAS  PubMed  Google Scholar 

  • Su GH, Hilgers W, Shekher MC, Tang DJ, Yeo CJ, Hurban RH et al. (1998). Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene. Cancer Res 58: 2339–2342.

    CAS  PubMed  Google Scholar 

  • Sugio K, Kishimoto Y, Virmani AK, Hung JY, Gazdar AF . (1992). Kras gene mutations as a prognostic marker in adenocarcinoma of the human lung without lymph node metastasis. Cancer Res 52: 339–346.20.

    Google Scholar 

  • Teng DH, Perry III WL, Hogan JK, Baumgard M, Bell R, Berry S et al. (1997). Human mitogen-activated protein kinase kinase 4 as a candidate tumor suppressor. Cancer Res 57: 4177–4182.

    CAS  PubMed  Google Scholar 

  • Vicent S, Garayoa M, Lopez-Picazo JM, Lozano MD, Toledo G, Thunnisen FBJM et al. (2004). Mitogen-activated protein kinase phosphatase-1 is overexpressed in non-small cell lung cancer and is an independent predictor of outcome in patients. Clin Cancer Res 10: 3639–3649.

    Article  CAS  Google Scholar 

  • Wang L, Pan Y, Dai JL . (2004). Evidence of MKK4 pro-oncogenic activity in breast and pancreatic tumors. Oncogene 23: 5978–5985.

    Article  CAS  Google Scholar 

  • Xiao L, Lang W . (2000). A dominant role for the Jun N-terminal kinase in oncogenic ras-induced morphologic transformation of human lung carcinoma cells. Cancer Res 60: 400–408.

    CAS  PubMed  Google Scholar 

  • Yamada SD, Hickson JA, Hrobowski Y, Vander Griend DJ, Benson D, Montag A et al. (2002). Mitogen-activated protein kinase kinase 4 (MKK4) acts as a metastasis suppressor gene in human ovarian carcinoma. Cancer Res 62: 6717–6723.

    CAS  PubMed  Google Scholar 

  • Yang YM, Bost F, Charbono W, Yang YM, Bost F, Charbono W et al. (2003). C-Jun NH(2)-terminal kinase mediates proliferation and tumor growth of human prostate carcinoma. Clin Cancer Res 9: 391–401.

    CAS  PubMed  Google Scholar 

  • Zhong CY, Zhou YM, Douglas GC, Witschi H, Pinkerton KE . (2005). MAPK/AP-1 signal pathway in tobacco smoke-induced cell proliferation and squamous metaplasia in the lungs of rats. Carcinogenesis 26: 2187–2195.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by National Institutes of Health Grants R01 CA105155 and P50 CA70907.

Author information

Authors and Affiliations

  1. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    T S Khatlani, M Sun, H Srinivas, K Iwanaga, A E Hanna, I I Wistuba & J M Kurie

  2. Department of Pulmonology, AP-HP, Hopital Tenon, Paris, France

    M Wislez & J D Minna

  3. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    M Sun

  4. Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    L Ma & I I Wistuba

  5. Department of Biostatistics and Applied Mathematics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    D Liu

  6. Hamon Center for Therapeutic Oncology Research, University of Texas-Southwestern Medical Center, Dallas, TX, USA

    L Girard

  7. Department of Pathology, Stanford University School of Medicine, Stanford, California, USA

    Y H Kim & J R Pollack

Authors
  1. T S Khatlani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Wislez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H Srinivas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K Iwanaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A E Hanna
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. L Girard
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Y H Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. J R Pollack
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. J D Minna
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. I I Wistuba
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. J M Kurie
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J M Kurie.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Khatlani, T., Wislez, M., Sun, M. et al. c-Jun N-terminal kinase is activated in non-small-cell lung cancer and promotes neoplastic transformation in human bronchial epithelial cells. Oncogene 26, 2658–2666 (2007). https://doi.org/10.1038/sj.onc.1210050

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210050

Keywords

This article is cited by

Search

Advanced search

Quick links