Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
권호 표지
DOI QR코드

DOI QR Code

O-GlcNAcylation of NF-κB Promotes Lung Metastasis of Cervical Cancer Cells via Upregulation of CXCR4 Expression

  • Ali, Akhtar (Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University, School of Medicine) ;
  • Kim, Sung Hwan (Department of Thoriac and Cardiovascular Surgery, Gyeongsang National University, School of Medicine) ;
  • Kim, Min Jun (Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University, School of Medicine) ;
  • Choi, Mee Young (Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University, School of Medicine) ;
  • Kang, Sang Soo (Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University, School of Medicine) ;
  • Cho, Gyeong Jae (Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University, School of Medicine) ;
  • Kim, Yoon Sook (Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University, School of Medicine) ;
  • Choi, Jun-Young (Department of Thoriac and Cardiovascular Surgery, Gyeongsang National University, School of Medicine) ;
  • Choi, Wan Sung (Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University, School of Medicine)
  • Received : 2017.05.31
  • Accepted : 2017.06.05
  • Published : 2017.07.31
Download PDF
⟨ Previous Next ⟩

Abstract

C-X-C chemokine receptor 4 (CXCR4) stimulates cancer metastasis. NF-${\kappa}B$ regulates CXCR4 expression in cancer cells, and O-GlcNAc modification of NF-${\kappa}B$ promotes its transcriptional activity. Here, we determined whether CXCR4 expression is affected by O-GlcNAcylation of NF-${\kappa}B$ in lung metastasis of cervical cancer. We found elevated levels of O-linked-N-actylglucosamine transferase (OGT) and O-GlcNAcylation in cervical cancer cells compared to those in non-malignant epithelial cells and detected increased expression of NF-${\kappa}B$ p65 (p65) and CXCR4 in cervical cancer cells. Knockdown of OGT inhibited the O-GlcNAcylation of p65 and decreased CXCR4 expression levels in HeLa cells. Thiamet G treatment increased O-GlcNAcylated p65, which subsequently enhanced CXCR4 expression levels. Inhibition of O-GlcNAcylation by 6-Diazo-5-oxo-L-norleucine (DON) treatment decreased p65 activation, eventually inhibiting CXCR4 expression in HeLa cells. Lung tissues from mice engrafted with OGT-knockdown HeLa cells (shOGT) exhibited lower expression of Ki-67 and HPV E6 and E7 oncogenes compared to lung tissues from mice engrafted with control HeLa cells (shCTL). In addition, lung tissues from mice engrafted with shOGT cells exhibited lower p65 and CXCR4 immunoreactivity compared to tissues from mice engrafted with shCTL cells. Taken together, our data suggest that p65 O-GlcNAcylation promotes lung metastasis of cervical cancer cells by activating CXCR4 expression.

Keywords

References

  1. Anderson, T.M., McMahon, J.J., Nwogu, C.E., Pombo, M.W., Urschel, J.D., Driscoll, D.L., and Lele, S.B. (2001). Pulmonary resection in metastatic uterine and cervical malignancies. Gynecol. Oncol. 83, 472-476. https://doi.org/10.1006/gyno.2001.6427
  2. Cai, Z., Tchou-Wong, K.M., and Rom, W.N. (2011). NF-kappaB in lung tumourigenesis. Cancers 3, 4258-4268. https://doi.org/10.3390/cancers3044258
  3. Chambers, A.F., Groom, A.C., and MacDonald, I.C. (2002). Dissemination and growth of cancer cells in metastatic sites. Nat. Rev. Cancer. 2, 563-572. https://doi.org/10.1038/nrc865
  4. DeFilippis,R.A., Goodwin, E.C., Wu, L., and DiMaio, D. (2003). Endogenous human papillomavirus E6 and E7 proteins differentially regulate proliferation, senescence, and apoptosis in HeLa cervical carcinoma cells. J. Viol. 77, 1551-1563.
  5. Dolcet, X., Llobet, D., Pallares, J., and Matias-Guiu, X. (2005). NF-${\kappa}B$ in development and progression of human cancer. Virchows. Arch. 446, 475-482. https://doi.org/10.1007/s00428-005-1264-9
  6. Esencay, M., Newcomb, E.W., and Zagzag, D. (2010). HGF upregulates CXCR4 expression in gliomas via NF-kappaB. Implications for glioma cell migration. J. Neurooncol. 99, 33-40. https://doi.org/10.1007/s11060-010-0111-2
  7. Fardini, Y., Dehennaut, V., Lefebvre, T., and Issad, T. (2013). OGlcNAcylation. A new cancer hallmark? Front. Endocrinol. 4, 1-14.
  8. Helbig, G., Christopherson, K.W., Bhat-Nakshatri, P., Kumar, S., Kishimoto, H., Miller, K.D., Broxmeyer, H.E., and Nakshatri, H. (2003). NF-kappaB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. J. Biol. Chem. 278, 21631-21638. https://doi.org/10.1074/jbc.M300609200
  9. Jozwiak, P., Forma, E., Brys, M., and Krzeslak, A. (2014). OGlcNAcylation and metabolic reprograming in cancer. Front. Endocrinol. 5, 1-13.
  10. Kato, M., Kitayama, J., Kazama, S., and Nagawa, H. (2003). Expression pattern of CXC chemokine receptor-4 is correlated with lymph node metastasis in human invasive ductal carcinoma. Breast Cancer. Res. 5, 144-150. https://doi.org/10.1186/bcr627
  11. Kucia, M., Jankowski, K., Reca, R., Wysoczynski, M., Bandura, L., Allendorf, D.J., Zhang, J., Ratajczak, J., and Ratajczak, M.Z. (2004). CXCR4-SDF-1 signalling, locomotion, chemotaxis and adhesion. J. Mol. Histol. 35, 233-245.
  12. Ma, Z., Vocadlo, D.J., and Vosseller, K. (2013). Hyper-OGlcNAcylation is anti-apoptotic and maintains constitutive NF-kappaB activity in pancreatic cancer cells. J. Biol. Chem. 288, 15121-15130. https://doi.org/10.1074/jbc.M113.470047
  13. Nair, A., Venkatraman, M., Maliekal, T.T., Nair, B., and Karunagaran, D. (2003). NF-kappaB is constitutively activated in high grade squamous intraepithelial lesions and squamous cell carcinomas of the human uterine cervix. Oncogene 22, 50-58. https://doi.org/10.1038/sj.onc.1206043
  14. Reinhardt, M.J., Ehritt-Braun, C., Vogelgesang, D., Ihling, C., Hogerle, S., Mix, M., Moser, E., and Krause, T.M. (2001). Metastatic lymph nodes in patients with cervical cancer: detection with MR imaging and FDFG PET. Radiology 218, 776-782. https://doi.org/10.1148/radiology.218.3.r01mr19776
  15. Sekula, M., Miekus, K., and Majka, M. (2014). Downregulation of the CXCR4 receptor inhibits cervical carcinoma metastatic behavior in vitro and in vivo. Int. J. Oncol. 44, 1853-1860. https://doi.org/10.3892/ijo.2014.2383
  16. Siegel, R.L., Miller,K.D., and Jemal, A. (2015). Cancer statistics, 2015. CA. Cancer. J. Clin. 65, 5-29. https://doi.org/10.3322/caac.21254
  17. Sironi, S., Buda, A., Picchio, M., Perego, P., Moreni, R., Pellegrino, A., Colombo, M., Mangioni, C., Messa, C., and Fazio, F. (2006). Lymph node metastasis in patients with clinical early-stage cervical cancer. Detection with integrated FDG PET/CT. Radiology 238, 272-279. https://doi.org/10.1148/radiol.2381041799
  18. Spano, D., Heck, C., De Antonellis, P., Christofori, G., and Zollo, M. (2012). Molecular networks that regulate cancer metastasis. Semin. Cancer. Biol. 22, 234-249. https://doi.org/10.1016/j.semcancer.2012.03.006
  19. Taichman, R.S., Cooper, C., Keller, E.T., Pienta, K.J., Taichman, N.S., and McCauley, L.K. (2002). Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. Cancer. Res. 62, 1832-1837.
  20. Tellis, C.J., and Beechler, C.R. (1982). Pulmonary metastasis of carcinoma of the cervix: a retrospective study. Cancer 49, 705-1709.
  21. Thanapprapasr, D., Nartthanarung, A., Likittanasombut, P., Na Ayudhya, N.I., Charakorn, C., Udomsubpayakul, U., Subhadarbandhu, T., and Wilailak, S. (2010). Bone metastasis in cervical cancer patients over a 10-year period. Int. J. Gynecol. Cancer 20, 373-378. https://doi.org/10.1111/IGC.0b013e3181d4a0a1
  22. Wang, X., and Adjei, A.A. (2015). Lung cancer and metastasis:New opportunities and challenges. Cancer Metastasis. Rev. 34, 169-171. https://doi.org/10.1007/s10555-015-9562-4
  23. Yang, W.H., Park, S.Y., Nam, H.W., Kim, D.H., Kang, J.G., Kang, E.S., Kim, Y.S., Lee, H.C., Kim, K.S., and Cho, J.W. (2008). NF-kappaB activation is associated with its O-GlcNAcylation state under hyperglycemic conditions. Proc. Natl. Acad. Sci. USA 105, 17345-17350. https://doi.org/10.1073/pnas.0806198105
  24. Zhi, Y., Lu, H., Duan, Y., Sun, W., Guan, G., Dong, Q., and Yang, C. (2015). Involvement of the Nuclear Factor-KappaB signaling pathway in the regulation of CXC chemokine receptor-4 expression in neuroblastoma cells induced by tumor necrosis factor-alpha. Int. J. Mol. Med. 35, 349-357. https://doi.org/10.3892/ijmm.2014.2032
  25. Zlotnik., A. (2006a). Chemokines and cancer: Int. J. Cancer. 119, 2026-2029. https://doi.org/10.1002/ijc.22024
  26. Zlotnik., A. (2006b). Involvement of chemokine receptors in organspecific metastasis. Contrib. Microbiol.13,191-199.
  27. Zlotnik., A. (2008). New insights on the role of CXCR4 in cancer metastasis. J. Pathol. 215, 211-213. https://doi.org/10.1002/path.2350

Cited by

  1. Role of miR-520b in non-small cell lung cancer vol.16, pp.5, 2018, https://doi.org/10.3892/etm.2018.6732
  2. NF-κB signaling and crosstalk during carcinogenesis vol.2, pp.None, 2017, https://doi.org/10.1051/fopen/2019010
  3. Eugenol inhibits non‐small cell lung cancer by repressing expression of NF‐κB‐regulated TRIM59 vol.33, pp.5, 2017, https://doi.org/10.1002/ptr.6352
  4. Hyperglycemia-Induced Aberrant Cell Proliferation; A Metabolic Challenge Mediated by Protein O-GlcNAc Modification vol.8, pp.9, 2017, https://doi.org/10.3390/cells8090999
  5. Molecular Mechanisms of Anticancer Activities of Puerarin vol.12, pp.None, 2020, https://doi.org/10.2147/cmar.s233567
  6. CFTR Regulates the Proliferation, Migration and Invasion of Cervical Cancer Cells by Inhibiting the NF-κB Signalling Pathway vol.12, pp.None, 2017, https://doi.org/10.2147/cmar.s252296
  7. Functional Analysis of O -GlcNAcylation in Cancer Metastasis vol.10, pp.None, 2017, https://doi.org/10.3389/fonc.2020.585288
  8. Quercetin and cervical cancer: a view of great scope vol.29, pp.11, 2020, https://doi.org/10.1007/s00044-020-02622-4
  9. O-GlcNAcylation in Chronic Lymphocytic Leukemia and Other Blood Cancers vol.12, pp.None, 2017, https://doi.org/10.3389/fimmu.2021.772304
  10. Regulation of Nuclear Factor-kappaB Function by O-GlcNAcylation in Inflammation and Cancer vol.9, pp.None, 2017, https://doi.org/10.3389/fcell.2021.751761
  11. Glycosylation in Cervical Cancer: New Insights and Clinical Implications vol.11, pp.None, 2021, https://doi.org/10.3389/fonc.2021.706862
  12. Protein Substrates Engage the Lumen of O-GlcNAc Transferase’s Tetratricopeptide Repeat Domain in Different Ways vol.60, pp.11, 2021, https://doi.org/10.1021/acs.biochem.0c00981
  13. Role and Function of O-GlcNAcylation in Cancer vol.13, pp.21, 2017, https://doi.org/10.3390/cancers13215365
  14. O-GlcNAcylation protein disruption by Thiamet G promotes changes on the GBM U87-MG cells secretome molecular signature vol.18, pp.1, 2017, https://doi.org/10.1186/s12014-021-09317-x