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:

TOPK/PBK promotes cell migration via modulation of the PI3K/PTEN/AKT pathway and is associated with poor prognosis in lung cancer

Oncogene volume 31, pages 2389–2400 (2012)Cite this article

Abstract

We integrated four gene expression profile data sets, namely two different pair-matched stage I lung adenocarcinoma data sets, secondary metastatic tumors vs benign tumors and lung tumor metastasizes to the brain, and we identified one kinase, T-LAK Cell-Originated Protein Kinase (TOPK), as a putative gene that promotes metastasis. To delineate the role of TOPK in lung cancer, we showed that overexpression of TOPK, but not a catalytically inactive form of TOPK, can enhance the migration and invasion of lung fibroblasts or cells with low TOPK expression. In addition, TOPK-induced cell migration was shown to be a PI3K/AKT-dependent event. TOPK concurrently promoted AKT phosphorylation at Ser473 and decreased the phosphatase and tensin homolog (PTEN) levels, whereas TOPK knockdown had the reverse effects. LY294002, a PI3K inhibitor, did not inhibit the TOPK-induced decrease in PTEN, and co-expression of PTEN significantly reduced TOPK-induced AKT phosphorylation in a dose-dependent manner; these results indicate that the TOPK-mediated PTEN decrease has an upstream role in regulating PI3K/AKT-stimulated migration. Using immunohistochemical analysis of lung cancer tissue samples, we showed that a high TOPK expression level correlates strongly with reduced overall and disease-free survivals. Moreover, an inverse correlation between TOPK and PTEN expression was present and is consistent with the biochemical findings. Finally, a combination of high TOPK and low PTEN expression was inversely correlated with overall and disease-free survivals, independent of other pathologic staging factors. Our results suggest that TOPK is a potential therapeutic target in lung cancer that promotes cell migration by modulating a PI3K/PTEN/AKT-dependent signaling pathway; they also suggest that high TOPK expression, either alone or in combination with a low level of PTEN, may serve as a prognostic marker for lung cancer.

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
Figure 7
Figure 8

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  • Abe Y, Matsumoto S, Kito K, Ueda N . (2000). Cloning and expression of a novel MAPKK-like protein kinase, lymphokine-activated killer T-cell-originated protein kinase, specifically expressed in the testis and activated lymphoid cells. J Biol Chem 275: 21525–21531.

    Article  CAS  Google Scholar 

  • Abe Y, Takeuchi T, Kagawa-Miki L, Ueda N, Shigemoto K, Yasukawa M et al. (2007). A mitotic kinase TOPK enhances Cdk1/cyclin B1-dependent phosphorylation of PRC1 and promotes cytokinesis. J Mol Biol 370: 231–245.

    Article  CAS  Google Scholar 

  • Akca H, Demiray A, Tokgun O, Yokota J . (2011). Invasiveness and anchorage independent growth ability augmented by PTEN inactivation through the PI3K/AKT/NFkB pathway in lung cancer cells. Lung Cancer 73: 302–309.

    Article  Google Scholar 

  • al-Kattan K, Sepsas E, Fountain SW, Townsend ER . (1997). Disease recurrence after resection for stage I lung cancer. Eur J Cardiothorac Surg 12: 380–384.

    Article  CAS  Google Scholar 

  • Arriagada R, Auperin A, Burdett S, Higgins JP, Johnson DH, Le Chevalier T et al. (2010). Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data. Lancet 375: 1267–1277.

    Article  CAS  Google Scholar 

  • Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J . (2004). Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350: 351–360.

    Article  Google Scholar 

  • Ayllon V, O'Connor R . (2007). PBK/TOPK promotes tumour cell proliferation through p38 MAPK activity and regulation of the DNA damage response. Oncogene 26: 3451–3461.

    Article  CAS  Google Scholar 

  • Chalhoub N, Baker SJ . (2009). PTEN and the PI3-kinase pathway in cancer. Annu Rev Pathol 4: 127–150.

    Article  CAS  Google Scholar 

  • Chen CH, Lai JM, Chou TY, Chen CY, Su LJ, Lee YC et al. (2009a). VEGFA upregulates FLJ10540 and modulates migration and invasion of lung cancer via PI3K/AKT pathway. PLoS ONE 4: e5052.

    Article  Google Scholar 

  • Chen TC, Lee SA, Hong TM, Shih JY, Lai JM, Chiou HY et al. (2009b). From midbody protein-protein interaction network construction to novel regulators in cytokinesis. J Proteome Res 8: 4943–4953.

    Article  CAS  Google Scholar 

  • Friedl P, Wolf K . (2003). Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer 3: 362–374.

    Article  CAS  Google Scholar 

  • Furnari FB, Lin H, Huang HS, Cavenee WK . (1997). Growth suppression of glioma cells by PTEN requires a functional phosphatase catalytic domain. Proc Natl Acad Sci USA 94: 12479–12484.

    Article  CAS  Google Scholar 

  • Gaudet S, Branton D, Lue RA . (2000). Characterization of PDZ-binding kinase, a mitotic kinase. Proc Natl Acad Sci USA 97: 5167–5172.

    Article  CAS  Google Scholar 

  • Herrero-Martin D, Osuna D, Ordonez JL, Sevillano V, Martins AS, Mackintosh C et al. (2009). Stable interference of EWS-FLI1 in an Ewing sarcoma cell line impairs IGF-1/IGF-1R signalling and reveals TOPK as a new target. Br J Cancer 101: 80–90.

    Article  CAS  Google Scholar 

  • Hu F, Gartenhaus RB, Eichberg D, Liu Z, Fang HB, Rapoport AP . (2010). PBK/TOPK interacts with the DBD domain of tumor suppressor p53 and modulates expression of transcriptional targets including p21. Oncogene 29: 5464–5474.

    Article  CAS  Google Scholar 

  • Hung JJ, Hsu WH, Hsieh CC, Huang BS, Huang MH, Liu JS et al. (2009). Post-recurrence survival in completely resected stage I non-small cell lung cancer with local recurrence. Thorax 64: 192–196.

    Article  Google Scholar 

  • Kratz JR, Jablons DM . (2009). Genomic prognostic models in early-stage lung cancer. Clin Lung Cancer 10: 151–157.

    Article  CAS  Google Scholar 

  • Matsumoto S, Abe Y, Fujibuchi T, Takeuchi T, Kito K, Ueda N et al. (2004). Characterization of a MAPKK-like protein kinase TOPK. Biochem Biophys Res Commun 325: 997–1004.

    Article  CAS  Google Scholar 

  • Nandi A, Tidwell M, Karp J, Rapoport AP . (2004). Protein expression of PDZ-binding kinase is up-regulated in hematologic malignancies and strongly down-regulated during terminal differentiation of HL-60 leukemic cells. Blood Cells Mol Dis 32: 240–245.

    Article  CAS  Google Scholar 

  • Nandi AK, Ford T, Fleksher D, Neuman B, Rapoport AP . (2007). Attenuation of DNA damage checkpoint by PBK, a novel mitotic kinase, involves protein-protein interaction with tumor suppressor p53. Biochem Biophys Res Commun 358: 181–188.

    Article  CAS  Google Scholar 

  • Oh SM, Zhu F, Cho YY, Lee KW, Kang BS, Kim HG et al. (2007). T-lymphokine-activated killer cell-originated protein kinase functions as a positive regulator of c-Jun-NH2-kinase 1 signaling and H-Ras-induced cell transformation. Cancer Res 67: 5186–5194.

    Article  CAS  Google Scholar 

  • Omuro AM, Kris MG, Miller VA, Franceschi E, Shah N, Milton DT et al. (2005). High incidence of disease recurrence in the brain and leptomeninges in patients with nonsmall cell lung carcinoma after response to gefitinib. Cancer 103: 2344–2348.

    Article  CAS  Google Scholar 

  • Park JH, Lin ML, Nishidate T, Nakamura Y, Katagiri T . (2006). PDZ-binding kinase/T-LAK cell-originated protein kinase, a putative cancer/testis antigen with an oncogenic activity in breast cancer. Cancer Res 66: 9186–9195.

    Article  CAS  Google Scholar 

  • Simons-Evelyn M, Bailey-Dell K, Toretsky JA, Ross DD, Fenton R, Kalvakolanu D et al. (2001). PBK/TOPK is a novel mitotic kinase which is upregulated in Burkitt's lymphoma and other highly proliferative malignant cells. Blood Cells Mol Dis 27: 825–829.

    Article  CAS  Google Scholar 

  • Soria JC, Lee HY, Lee JI, Wang L, Issa JP, Kemp BL et al. (2002). Lack of PTEN expression in non-small cell lung cancer could be related to promoter methylation. Clin Cancer Res 8: 1178–1184.

    CAS  Google Scholar 

  • Strauss GM, Herndon 2nd JE, Maddaus MA, Johnstone DW, Johnson EA, Harpole DH et al. (2008). Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 26: 5043–5051.

    Article  CAS  Google Scholar 

  • Su LJ, Chang CW, Wu YC, Chen KC, Lin CJ, Liang SC et al. (2007). Selection of DDX5 as a novel internal control for Q-RT-PCR from microarray data using a block bootstrap re-sampling scheme. BMC Genomics 8: 140.

    Article  CAS  Google Scholar 

  • Sugimura H, Nichols FC, Yang P, Allen MS, Cassivi SD, Deschamps C et al. (2007). Survival after recurrent nonsmall-cell lung cancer after complete pulmonary resection. Ann Thorac Surg 83: 409–417; discussion 417–408.

    Article  Google Scholar 

  • Vivanco I, Sawyers CL . (2002). The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer 2: 489–501.

    Article  CAS  Google Scholar 

  • Wang X, Trotman LC, Koppie T, Alimonti A, Chen Z, Gao Z et al. (2007). NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell 128: 129–139.

    Article  CAS  Google Scholar 

  • Zhu F, Zykova TA, Kang BS, Wang Z, Ebeling MC, Abe Y et al. (2007). Bidirectional signals transduced by TOPK-ERK interaction increase tumorigenesis of HCT116 colorectal cancer cells. Gastroenterology 133: 219–231.

    Article  CAS  Google Scholar 

  • Zlobec I, Molinari F, Kovac M, Bihl MP, Altermatt HJ, Diebold J et al. (2010). Prognostic and predictive value of TOPK stratified by KRAS and BRAF gene alterations in sporadic, hereditary and metastatic colorectal cancer patients. Br J Cancer 102: 151–161.

    Article  CAS  Google Scholar 

  • Zykova TA, Zhu F, Lu C, Higgins L, Tatsumi Y, Abe Y et al. (2006). Lymphokine-activated killer T-cell-originated protein kinase phosphorylation of histone H2AX prevents arsenite-induced apoptosis in RPMI7951 melanoma cells. Clin Cancer Res 12: 6884–6893.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr Chi-Ying F Huang (Yang-Ming University, Taipei, Taiwan) for providing lung cancer microarray data. This work was supported by grants from National Science Council (Taiwan) (NSC95-2311-B-030-002-MY3 and NSC99-2627-B-030-001) to JM Lai and Center of Excellence for Cancer Research at Taipei Veterans General Hospital (DOH100-TD-C-111-007) to YC Wu.

Author information

Author notes

  1. M-C Shih, J-Y Chen, Y-C Wu and Y-H Jan: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Life Science, College of Science and Engineering, Fu Jen Catholic University, New Taipei City, Taiwan

    M-C Shih, J-Y Chen, B-M Yang & J-M Lai

  2. Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan

    Y-C Wu

  3. Genomics Research Center, Academia Sinica, Taipei, Taiwan

    Y-H Jan & M Hsiao

  4. Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    P-J Lu & H-C Cheng

  5. Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

    M-S Huang & C-J Yang

Authors
  1. M-C Shih
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J-Y Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y-C Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y-H Jan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B-M Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P-J Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H-C Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M-S Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C-J Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M Hsiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. J-M Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J-M Lai.

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

Shih, MC., Chen, JY., Wu, YC. et al. TOPK/PBK promotes cell migration via modulation of the PI3K/PTEN/AKT pathway and is associated with poor prognosis in lung cancer. Oncogene 31, 2389–2400 (2012). https://doi.org/10.1038/onc.2011.419

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2011.419

Keywords

This article is cited by

Search

Advanced search

Quick links