Advertisement

Tumor Biology

, Volume 35, Issue 10, pp 10443–10448 | Cite as

Melittin enhances radiosensitivity of hypoxic head and neck squamous cell carcinoma by suppressing HIF-1α

  • Xi Yang
  • Hongcheng Zhu
  • Yangyang Ge
  • Jia Liu
  • Jing Cai
  • Qin Qin
  • Liangliang Zhan
  • Chi Zhang
  • Liping Xu
  • Zheming Liu
  • Yan Yang
  • Yuehua Yang
  • Jianxin Ma
  • Hongyan Cheng
  • Xinchen Sun
Research Article

Abstract

Hypoxia is a widespread phenomenon present in many human solid tumors and is associated with a poor prognosis and therapy resistance. Here, we tested the feasibility of melittin, a major component of bee venom, on radiosensitization of hypoxic head and neck squamous cell carcinoma (HNSCC). CNE-2 and KB cells were treated with melittin and radiation response was determined. Cell viability, cytotoxicity and apoptosis induction were examined by CCK-8 assay, colony formation assay, and flow cytometry. Expression of hypoxia-inducible factor 1-alpha (HIF-1α) and vascular endothelial growth factor (VEGF) proteins were assessed using western blotting. Additionally, we also examined the effect of melittin on tumor growth and radiosensitivity in vivo using a xenograft model of HNSCC. Treatment with melittin resulted in cell growth inhibition, induction of cell apoptosis, and reduction of HIF-1α and VEGF expression, which has been linked to hypoxia cell radioresistance. In addition, intraperitoneal injection of melittin significantly reduced the growth of HNSCC tumors in CNE-2 tumor-bearing mice. These data suggest that melittin enhances radiosensitivity of HNSCC under hypoxia condition, and this is associated with the suppression of HIF-1α expression. Melittin appears to be a potential radiotherapy sensitization agent due to its significant antihypoxia activity.

Keywords

Melittin Head and neck squamous cell carcinoma Hypoxia Radiosensitivity HIF-1α 

Abbreviations

HNSCC

Head and neck squamous cell carcinomas

HIF-1α

Hypoxia-inducible factor-1α

VEGF

Vascular endothelial growth factor

Notes

Conflicts of interest

This study was supported by the Natural Science Foundation of China (No. 81272504), the Innovation Team (No. LJ201123-EH11), Jiangsu Provincial Science and Technology Projects BK2011854 (DA11), the Six Major Talent Peak Project of Jiangsu Province, a project funded by the priority academic program development of Jiangsu Higher Education Institution (JX10231801), grants from Key Academic Discipline of Jiangsu Province “Medical Aspects of Specific Environments”, the Research and Innovation Project for College Graduates of Jiangsu Province (no. CXLX13_572) and “333” Project of Jiangsu Province BRA2012210 (RS12). The authors declare that there are no known conflicts of interest associated with this publication.

References

  1. 1.
    Bauer VL, Hieber L, Schaeffner Q, Weber J, Braselmann H, Huber R, et al. Establishment and molecular cytogenetic characterization of a cell culture model of head and neck squamous cell carcinoma (HNSCC). Genes. 2010;1:388–412.PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Bittner MI, Grosu AL. Hypoxia in head and neck tumors: characteristics and development during therapy. Frontiers Oncology. 2013;3:223.Google Scholar
  3. 3.
    Semenza GL. Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu Rev Pathol. 2014;9:47–71.CrossRefPubMedGoogle Scholar
  4. 4.
    Yang X, Zhang C, Zhu HC, Qin Q, Zhao LJ, Liu J, et al. HIF-1alpha P582S and A588T polymorphisms and digestive system cancer risk-a meta-analysis. Tumour Biol: J Int Soc Oncodevelopmental Biol Med. 2014;35:2825–30.CrossRefGoogle Scholar
  5. 5.
    Yang X, Zhu HC, Zhang C, Qin Q, Liu J, Xu LP, et al. HIF-1alpha 1772 C/T and 1790 G/A polymorphisms are significantly associated with higher cancer risk: an updated meta-analysis from 34 case-control studies. PLoS One. 2013;8:e80396.PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Sadri N, Zhang PJ. Hypoxia-inducible factors: mediators of cancer progression; prognostic and therapeutic targets in soft tissue sarcomas. Cancers. 2013;5:320–33.PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Ge X, Zhen F, Yang B, Yang X, Cai J, Zhang C, et al. Ginsenoside Rg3 enhances radiosensitization of hypoxic oesophageal cancer cell lines through vascular endothelial growth factor and hypoxia inducible factor 1alpha. J Int Med Res. 2014;42(3):628–40.CrossRefPubMedGoogle Scholar
  8. 8.
    Yang X, Yang B, Cai J, Zhang C, Zhang Q, Xu L, et al. Berberine enhances radiosensitivity of esophageal squamous cancer by targeting HIF-1alpha in vitro and in vivo. Cancer Biol Ther. 2013;14:1068–73.PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Zhang C, Yang X, Zhang Q, Yang B, Xu L, Qin Q, et al. Berberine radiosensitizes human nasopharyngeal carcinoma by suppressing hypoxia-inducible factor-1alpha expression. Acta Otolaryngol. 2014;134:185–92.CrossRefPubMedGoogle Scholar
  10. 10.
    Raghuraman H, Chattopadhyay A. Melittin: a membrane-active peptide with diverse functions. Biosci Rep. 2007;27:189–223.CrossRefPubMedGoogle Scholar
  11. 11.
    Gajski G, Garaj-Vrhovac V. Melittin: a lytic peptide with anticancer properties. Environ Toxicol Pharmacol. 2013;36:697–705.CrossRefPubMedGoogle Scholar
  12. 12.
    Shin JM, Jeong YJ, Cho HJ, Park KK, Chung IK, Lee IK, et al. Melittin suppresses HIF-1alpha/VEGF expression through inhibition of ERK and mTOR/p70S6K pathway in human cervical carcinoma cells. PLoS One. 2013;8:e69380.PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Wachters JE, Schrijvers ML, Slagter-Menkema L, Mastik M, de Bock GH, Langendijk JA, et al. Prognostic significance of HIF-1a, CA-IX, and OPN in T1-T2 laryngeal carcinoma treated with radiotherapy. Laryngoscope. 2013;123:2154–60.CrossRefPubMedGoogle Scholar
  14. 14.
    Wan XB, Fan XJ, Huang PY, Dong D, Zhang Y, Chen MY, et al. Aurora-A activation, correlated with hypoxia-inducible factor-1alpha, promotes radiochemoresistance and predicts poor outcome for nasopharyngeal carcinoma. Cancer Sci. 2012;103:1586–94.CrossRefPubMedGoogle Scholar
  15. 15.
    Hsu HW, Wall NR, Hsueh CT, Kim S, Ferris RL, Chen CS, et al. Combination antiangiogenic therapy and radiation in head and neck cancers. Oral Oncol. 2014;50:19–26.CrossRefPubMedGoogle Scholar
  16. 16.
    Huang PY, Sun ZY, Xie CM, Chen QY, Wen YF, Li J, et al. Prognostic significance of the various classifications for parapharyngeal space involvement in nasopharyngeal carcinoma. Acta Otolaryngol. 2012;132:1197–207.CrossRefPubMedGoogle Scholar
  17. 17.
    Xueguan L, Xiaoshen W, Yongsheng Z, Chaosu H, Chunying S, Yan F. Hypoxia inducible factor-1 alpha and vascular endothelial growth factor expression are associated with a poor prognosis in patients with nasopharyngeal carcinoma receiving radiotherapy with carbogen and nicotinamide. Clin Oncol. 2008;20:606–12.CrossRefGoogle Scholar
  18. 18.
    Hu H, Chen D, Li Y, Zhang X. Effect of polypeptides in bee venom on growth inhibition and apoptosis induction of the human hepatoma cell line SMMC-7721 in-vitro and Balb/c nude mice in-vivo. J Pharm Pharmacol. 2006;58:83–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Yang ZL, Ke YQ, Xu RX, Peng P. [Melittin inhibits proliferation and induces apoptosis of malignant human glioma cells]. Nan fang yi ke da xue xue bao J South Med Univ. 2007;27:1775–7.Google Scholar
  20. 20.
    Li B, Gu W, Zhang C, Huang XQ, Han KQ, Ling CQ. Growth arrest and apoptosis of the human hepatocellular carcinoma cell line BEL-7402 induced by melittin. Onkologie. 2006;29:367–71.CrossRefPubMedGoogle Scholar
  21. 21.
    Park JH, Jeong YJ, Park KK, Cho HJ, Chung IK, Min KS, et al. Melittin suppresses PMA-induced tumor cell invasion by inhibiting NF-kappaB and AP-1-dependent MMP-9 expression. Molecules and Cells. 2010;29:209–15.CrossRefPubMedGoogle Scholar
  22. 22.
    Jo M, Park MH, Kollipara PS, An BJ, Song HS, Han SB, et al. Anti-cancer effect of bee venom toxin and melittin in ovarian cancer cells through induction of death receptors and inhibition of JAK2/STAT3 pathway. Toxicol Appl Pharmacol. 2012;258:72–81.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Xi Yang
    • 1
  • Hongcheng Zhu
    • 1
  • Yangyang Ge
    • 2
  • Jia Liu
    • 1
  • Jing Cai
    • 2
  • Qin Qin
    • 1
  • Liangliang Zhan
    • 1
  • Chi Zhang
    • 1
  • Liping Xu
    • 1
  • Zheming Liu
    • 1
  • Yan Yang
    • 1
  • Yuehua Yang
    • 1
  • Jianxin Ma
    • 3
  • Hongyan Cheng
    • 4
  • Xinchen Sun
    • 1
  1. 1.Department of Radiation OncologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
  2. 2.Department of Radiation OncologyThe Affiliated Tumor Hospital of Nantong UniversityNantongChina
  3. 3.Department of Radiation Oncology, The Second People’s Hospital of LianYungangLianyungang Hospital Affiliated to Bengbu Medical CollegeLian YungangChina
  4. 4.Department of General Internal MedicineThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina

Personalised recommendations