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International Journal of Oncology
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Print ISSN: 1019-6439 Online ISSN: 1791-2423
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October 2012 Volume 41 Issue 4

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International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

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Article

The NEDD8 conjugation pathway regulates p53 transcriptional activity and head and neck cancer cell sensitivity to ionizing radiation

  • Authors:
    • Sébastien Guihard
    • Ludivine Ramolu
    • Christine Macabre
    • Bohdan  Wasylyk
    • Georges Noël
    • Joseph Abecassis
    • Alain C. Jung
  • View Affiliations / Copyright

    Affiliations: EA3430, Laboratory for Tumor Biology, Paul Strauss Cancer Center, F-67065 Strasbourg Cedex, France, IGBMC, UMR 7104 CNRS UDS - U 964 INSERM, F-67404 Illkirch Cedex, France
  • Pages: 1531-1540
    |
    Published online on: August 7, 2012
       https://doi.org/10.3892/ijo.2012.1584
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Abstract

Human papillomavirus (HPV)-related oropharyngeal cancer represents a distinct head and neck squamous cell carcinoma (HNSCC) subpopulation, with improved disease-free and overall survival. In general, HPV-positive HNSCCs express wild-type TP53, which could explain its increased radiosensitivity. However, the molecular mechanisms underlying this higher sensitivity remain elusive. We have previously shown that HPV-related oropharyngeal carcinomas express decreased levels of the NEDD8-activating enzyme 1/amyloid β precursor protein-binding protein 1 (NAE1/APP-BP1) gene. NAE1/APP-BP1 function is required for the NEDDylation of target proteins, and has been shown to be a negative regulator of p53 transcriptional activity. In this study, we addressed the hypothesis that NAE1/APP-BP1 expression levels regulate p53 activity and cell survival upon ionizing irradiation. We used the radiosensitive and naturally HPV16-infected UPCI:SCC90 cell line and the radioresistant and HPV-negative SQ20B cell line as the control. NAE1/APP-BP1 expression levels were modulated with expression constructs and siRNAs. Radiosensitivity was evaluated with clonogenic survival assays. p53 transcriptional activity was measured with a luciferase assay. The overexpression of NAE1/APP-BP1 in UPCI:SCC90 cells resulted in the increased NEDDylation of p53, inhibition of p53 activity and increased cell resistance to ionizing radiation. Conversely, the inhibition of NAE1/APP-BP1 expression in SQ20B cells induced p53-dependent cell death after treatment with X-rays. Taken together, these results indicate that NAE1/APP-BP1 and NEDDylation are invovled in modulating p53 activity and regulating its role in the response of cells to ionizing radiation. Our findings bring new insights in the molecular mechanisms underlying the increased radiosensitivity of HPV-related oropharyngeal tumors. This is of importance, as no reliable and robust predictive biomarkers for tumor response to radiotherapy are currently available. These results also have potential clinical significance, as drugs targeting NAE1/APP-BP1 have recently emerged as a novel therapeutic modality in cancer treatment.
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1 

Leemans CR, Braakhuis BJ and Brakenhoff RH: The molecular biology of head and neck cancer. Nat Rev Cancer. 11:9–22. 2011. View Article : Google Scholar

2 

Butz K, Whitaker N, Denk C, Ullmann A, Geisen C and Hoppe-Seyler F: Induction of the p53-target gene GADD45 in HPV-positive cancer cells. Oncogene. 18:2381–2386. 1999. View Article : Google Scholar : PubMed/NCBI

3 

Jung AC, Briolat J, Millon R, et al: Biological and clinical relevance of transcriptionally active human papillomavirus (HPV) infection in oropharynx squamous cell carcinoma. Int J Cancer. 126:1882–1894. 2010.PubMed/NCBI

4 

Klussmann JP, Mooren JJ, Lehnen M, et al: Genetic signatures of HPV-related and unrelated oropharyngeal carcinoma and their prognostic implications. Clin Cancer Res. 15:1779–1786. 2009. View Article : Google Scholar : PubMed/NCBI

5 

Gong L and Yeh ET: Identification of the activating and conjugating enzymes of the NEDD8 conjugation pathway. J Biol Chem. 274:12036–12042. 1999. View Article : Google Scholar : PubMed/NCBI

6 

Osaka F, Kawasaki H, Aida N, et al: A new NEDD8-ligating system for cullin-4A. Genes Dev. 12:2263–2268. 1998. View Article : Google Scholar : PubMed/NCBI

7 

Petroski MD and Deshaies RJ: Function and regulation of cullin-RING ubiquitin ligases. Nat Rev Mol Cell Biol. 6:9–20. 2005. View Article : Google Scholar : PubMed/NCBI

8 

Xirodimas DP, Saville MK, Bourdon JC, Hay RT and Lane DP: Mdm2-mediated NEDD8 conjugation of p53 inhibits its transcriptional activity. Cell. 118:83–97. 2004. View Article : Google Scholar : PubMed/NCBI

9 

Ragin CC, Reshmi SC and Gollin SM: Mapping and analysis of HPV16 integration sites in a head and neck cancer cell line. Int J Cancer. 110:701–709. 2004. View Article : Google Scholar : PubMed/NCBI

10 

Maalouf M, Alphonse G, Colliaux A, et al: Different mechanisms of cell death in radiosensitive and radioresistant p53 mutated head and neck squamous cell carcinoma cell lines exposed to carbon ions and x-rays. Int J Radiat Oncol Biol Phys. 74:200–209. 2009. View Article : Google Scholar : PubMed/NCBI

11 

Gupta AK, Lee JH, Wilke WW, et al: Radiation response in two HPV-infected head-and-neck cancer cell lines in comparison to a non-HPV-infected cell line and relationship to signaling through AKT. Int J Radiat Oncol Biol Phys. 74:928–933. 2009. View Article : Google Scholar : PubMed/NCBI

12 

Chen Y, McPhie DL, Hirschberg J and Neve RL: The amyloid precursor protein-binding protein APP-BP1 drives the cell cycle through the S-M checkpoint and causes apoptosis in neurons. J Biol Chem. 275:8929–8935. 2000. View Article : Google Scholar : PubMed/NCBI

13 

de Boer MA, Jordanova ES, Kenter GG, et al: High human papillomavirus oncogene mRNA expression and not viral DNA load is associated with poor prognosis in cervical cancer patients. Clin Cancer Res. 13:132–138. 2007.

14 

Garrison SP, Jeffers JR, Yang C, et al: Selection against PUMA gene expression in Myc-driven B-cell lymphomagenesis. Mol Cell Biol. 28:5391–5402. 2008. View Article : Google Scholar : PubMed/NCBI

15 

Franken NA, Rodermond HM, Stap J, Haveman J and van Bree C: Clonogenic assay of cells in vitro. Nat Protoc. 1:2315–2319. 2006. View Article : Google Scholar : PubMed/NCBI

16 

Abramoff MD, Magelhaes PJ and Ram SJ: Image processing with ImageJ. Biophotonics Int. 11:36–42. 2004.

17 

Rasband WS: ImageJ. National Institutes of Health; Bethesda, MA: http://rsb.info.nih.gov/ij/, 1997–2008.

18 

Kozarsky KF, McKinley DR, Austin LL, Raper SE, Stratford-Perricaudet LD and Wilson JM: In vivo correction of low density lipoprotein receptor deficiency in the Watanabe heritable hyperlipidemic rabbit with recombinant adenoviruses. J Biol Chem. 269:13695–13702. 1994.

19 

Lassen P: The role of Human papillomavirus in head and neck cancer and the impact on radiotherapy outcome. Radiother Oncol. 95:371–380. 2010. View Article : Google Scholar : PubMed/NCBI

20 

Abida WM, Nikolaev A, Zhao W, Zhang W and Gu W: FBXO11 promotes the Neddylation of p53 and inhibits its transcriptional activity. J Biol Chem. 282:1797–1804. 2007. View Article : Google Scholar : PubMed/NCBI

21 

Kim HJ, Kim SH, Shim SO, et al: Drosophila homolog of APP-BP1 (dAPP-BP1) interacts antagonistically with APPL during Drosophila development. Cell Death Differ. 14:103–115. 2007. View Article : Google Scholar

22 

Nakayama KI and Nakayama K: Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer. 6:369–381. 2006. View Article : Google Scholar : PubMed/NCBI

23 

Jia L, Yang J, Hao X, et al: Validation of SAG/RBX2/ROC2 E3 ubiquitin ligase as an anticancer and radiosensitizing target. Clin Cancer Res. 16:814–824. 2010. View Article : Google Scholar : PubMed/NCBI

24 

Watson IR, Blanch A, Lin DC, Ohh M and Irwin MS: Mdm2-mediated NEDD8 modification of TAp73 regulates its transactivation function. J Biol Chem. 281:34096–34103. 2006. View Article : Google Scholar : PubMed/NCBI

25 

Quiet CA, Weichselbaum RR and Grdina DJ: Variation in radiation sensitivity during the cell cycle of two human squamous cell carcinomas. Int J Radiat Oncol Biol Phys. 20:733–738. 1991. View Article : Google Scholar : PubMed/NCBI

26 

Tell R, Heiden T, Granath F, Borg AL, Skog S and Lewensohn R: Comparison between radiation-induced cell cycle delay in lymphocytes and radiotherapy response in head and neck cancer. Br J Cancer. 77:643–649. 1998. View Article : Google Scholar : PubMed/NCBI

27 

Milhollen MA, Traore T, Adams-Duffy J, et al: MLN4924, a NEDD8-activating enzyme inhibitor, is active in diffuse large B-cell lymphoma models: rationale for treatment of NF-κB-dependent lymphoma. Blood. 116:1515–1523. 2010.PubMed/NCBI

28 

Soucy TA, Smith PG, Milhollen MA, et al: An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature. 458:732–736. 2009. View Article : Google Scholar : PubMed/NCBI

29 

Ang KK, Harris J, Wheeler R, et al: Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 363:24–35. 2010. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Guihard S, Ramolu L, Macabre C, Wasylyk B, Noël G, Abecassis J and Jung AC: The NEDD8 conjugation pathway regulates p53 transcriptional activity and head and neck cancer cell sensitivity to ionizing radiation. Int J Oncol 41: 1531-1540, 2012.
APA
Guihard, S., Ramolu, L., Macabre, C., Wasylyk, B., Noël, G., Abecassis, J., & Jung, A.C. (2012). The NEDD8 conjugation pathway regulates p53 transcriptional activity and head and neck cancer cell sensitivity to ionizing radiation. International Journal of Oncology, 41, 1531-1540. https://doi.org/10.3892/ijo.2012.1584
MLA
Guihard, S., Ramolu, L., Macabre, C., Wasylyk, B., Noël, G., Abecassis, J., Jung, A. C."The NEDD8 conjugation pathway regulates p53 transcriptional activity and head and neck cancer cell sensitivity to ionizing radiation". International Journal of Oncology 41.4 (2012): 1531-1540.
Chicago
Guihard, S., Ramolu, L., Macabre, C., Wasylyk, B., Noël, G., Abecassis, J., Jung, A. C."The NEDD8 conjugation pathway regulates p53 transcriptional activity and head and neck cancer cell sensitivity to ionizing radiation". International Journal of Oncology 41, no. 4 (2012): 1531-1540. https://doi.org/10.3892/ijo.2012.1584
Copy and paste a formatted citation
x
Spandidos Publications style
Guihard S, Ramolu L, Macabre C, Wasylyk B, Noël G, Abecassis J and Jung AC: The NEDD8 conjugation pathway regulates p53 transcriptional activity and head and neck cancer cell sensitivity to ionizing radiation. Int J Oncol 41: 1531-1540, 2012.
APA
Guihard, S., Ramolu, L., Macabre, C., Wasylyk, B., Noël, G., Abecassis, J., & Jung, A.C. (2012). The NEDD8 conjugation pathway regulates p53 transcriptional activity and head and neck cancer cell sensitivity to ionizing radiation. International Journal of Oncology, 41, 1531-1540. https://doi.org/10.3892/ijo.2012.1584
MLA
Guihard, S., Ramolu, L., Macabre, C., Wasylyk, B., Noël, G., Abecassis, J., Jung, A. C."The NEDD8 conjugation pathway regulates p53 transcriptional activity and head and neck cancer cell sensitivity to ionizing radiation". International Journal of Oncology 41.4 (2012): 1531-1540.
Chicago
Guihard, S., Ramolu, L., Macabre, C., Wasylyk, B., Noël, G., Abecassis, J., Jung, A. C."The NEDD8 conjugation pathway regulates p53 transcriptional activity and head and neck cancer cell sensitivity to ionizing radiation". International Journal of Oncology 41, no. 4 (2012): 1531-1540. https://doi.org/10.3892/ijo.2012.1584
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