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Cannabinoid 2 receptor induction by IL-12 and its potential as a therapeutic target for the treatment of anaplastic thyroid carcinoma

Abstract

Anaplastic thyroid carcinoma is the most aggressive type of thyroid malignancies. Previously, we demonstrated that tumorigenicity of anaplastic thyroid carcinoma cell line ARO was significantly reduced following interleukin (IL)-12 gene transfer. We suspected that tumor target structure in ARO/IL-12 cells might be changed and such a change may make them more susceptible to be killed through mechanisms apart from natural killer-dependent pathway. To identify genes involved, we examined gene expression profile of ARO and ARO/IL-12 by microarray analysis of 3757 genes. The most highly expressed gene was cannabinoid receptor 2 (CB2), which was expressed eightfold higher in ARO/IL-12 cells than ARO cells. CB2 agonist JWH133 and mixed CB1/CB2 agonist WIN-55,212–2 could induce significantly higher rate of apoptosis in ARO/IL-12 than ARO cells. Similar results were obtained when ARO cells were transfected with CB2 transgene (ARO/CB2). A considerable regression of thyroid tumors generated by inoculation of ARO/CB2 cells was observed in nude mice following local administration of JWH133. We also demonstrated significant increase in the induction of apoptosis in ARO/IL12 and ARO/CB2 cells following incubation with 15 nM paclitaxel, indicating that tumor cells were sensitized to chemotherapy. These data suggest that CB2 overexpression may contribute to the regression of human anaplastic thyroid tumor in nude mice following IL-12 gene transfer. Given that cannabinoids have shown antitumor effects in many types of cancer models, CB2 may be a viable therapeutic target for the treatment of anaplastic thyroid carcinoma.

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References

  1. Hundahl SA, Fleming ID, Fremgen AM, Menck HR . A National Cancer Data Base report on 53 856 cases of thyroid carcinoma treated in the US 1985–1995 [see comments]. Cancer 1998; 83: 2638–2648.

    Article  CAS  Google Scholar 

  2. Farid NR, Shi Y, Zou M . Molecular basis of thyroid cancer. Endocr Rev 1994; 15: 202–232.

    CAS  PubMed  Google Scholar 

  3. Are C, Shaha AR . Anaplastic thyroid carcinoma: biology, pathogenesis, prognostic factors, and treatment approaches. Ann Surg Oncol 2006; 13: 453–464.

    Article  Google Scholar 

  4. Schott M, Scherbaum WA . Immunotherapy and gene therapy of thyroid cancer. Minerva Endocrinol 2004; 29: 175–187.

    CAS  PubMed  Google Scholar 

  5. Barzon L, Pacenti M, Boscaro M, Palu G . Gene therapy for thyroid cancer. Expert Opin Biol Ther 2004; 4: 1225–1239.

    Article  CAS  Google Scholar 

  6. Nanni P, Forni G, Lollini PL . Cytokine gene therapy: hopes and pitfalls. Ann Oncol 1999; 10: 261–266.

    Article  CAS  Google Scholar 

  7. Wysocki PJ, Karczewska-Dzionk A, Mackiewicz-Wysocka M, Mackiewicz A . Human cancer gene therapy with cytokine gene-modified cells. Expert Opin Biol Ther 2004; 4: 1595–1607.

    Article  CAS  Google Scholar 

  8. Sangro B, Melero I, Qian C, Prieto J . Gene therapy of cancer based on interleukin 12. Curr Gene Ther 2005; 5: 573–581.

    Article  CAS  Google Scholar 

  9. Shi Y, Parhar RS, Zou M, Baitei E, Kessie G, Farid NR et al. Gene therapy of anaplastic thyroid carcinoma with a single-chain interleukin-12 fusion protein. Hum Gene Ther 2003; 14: 1741–1751.

    Article  CAS  Google Scholar 

  10. Zou M, Famulski KS, Parhar RS, Baitei E, Al-Mohanna FA, Farid NR et al. Microarray analysis of metastasis-associated gene expression profiling in a murine model of thyroid carcinoma pulmonary metastasis: identification of S100A4 (Mts1) gene overexpression as a poor prognostic marker for thyroid carcinoma. J Clin Endocrinol Metab 2004; 89: 6146–6154.

    Article  CAS  Google Scholar 

  11. Shi Y, Zou M, Collison K, Baitei EY, Al-Makhalafi Z, Farid NR et al. Ribonucleic acid interference targeting S100A4 (Mts1) suppresses tumor growth and metastasis of anaplastic thyroid carcinoma in a mouse model. J Clin Endocrinol Metab 2006; 91: 2373–2379.

    Article  CAS  Google Scholar 

  12. Sanchez C, de Ceballos ML, del Pulgar TG, Rueda D, Corbacho C, Velasco G et al. Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. Cancer Res 2001; 61: 5784–5789.

    CAS  PubMed  Google Scholar 

  13. Airoldi I, Di Carlo E, Banelli B, Moserle L, Cocco C, Pezzolo A et al. The IL-12Rbeta2 gene functions as a tumor suppressor in human B cell malignancies. J Clin Invest 2004; 113: 1651–1659.

    Article  CAS  Google Scholar 

  14. Herrera B, Carracedo A, Diez-Zaera M, Gomez del Pulgar T, Guzman M, Velasco G . The CB2 cannabinoid receptor signals apoptosis via ceramide-dependent activation of the mitochondrial intrinsic pathway. Exp Cell Res 2006; 312: 2121–2131.

    Article  CAS  Google Scholar 

  15. Herrera B, Carracedo A, Diez-Zaera M, Guzman M, Velasco G . p38 MAPK is involved in CB2 receptor-induced apoptosis of human leukaemia cells. FEBS Lett 2005; 579: 5084–5088.

    Article  CAS  Google Scholar 

  16. Bacus SS, Gudkov AV, Lowe M, Lyass L, Yung Y, Komarov AP et al. Taxol-induced apoptosis depends on MAP kinase pathways (ERK and p38) and is independent of p53. Oncogene 2001; 20: 147–155.

    Article  CAS  Google Scholar 

  17. Guzman M . Cannabinoids: potential anticancer agents. Nat Rev Cancer 2003; 3: 745–755.

    Article  CAS  Google Scholar 

  18. Bifulco M, Laezza C, Pisanti S, Gazzerro P . Cannabinoids and cancer: pros and cons of an antitumour strategy. Br J Pharmacol 2006; 148: 123–135.

    Article  CAS  Google Scholar 

  19. Bifulco M, Di Marzo V . Targeting the endocannabinoid system in cancer therapy: a call for further research. Nat Med 2002; 8: 547–550.

    Article  CAS  Google Scholar 

  20. Blazquez C, Gonzalez-Feria L, Alvarez L, Haro A, Casanova ML, Guzman M . Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas. Cancer Res 2004; 64: 5617–5623.

    Article  CAS  Google Scholar 

  21. Vasko VV, Saji M . Molecular mechanisms involved in differentiated thyroid cancer invasion and metastasis. Curr Opin Oncol 2007; 19: 11–17.

    Article  CAS  Google Scholar 

  22. Xing M . BRAF mutation in thyroid cancer. Endocr Relat Cancer 2005; 12: 245–262.

    Article  CAS  Google Scholar 

  23. Powles T, te Poele R, Shamash J, Chaplin T, Propper D, Joel S et al. Cannabis-induced cytotoxicity in leukemic cell lines: the role of the cannabinoid receptors and the MAPK pathway. Blood 2005; 105: 1214–1221.

    Article  CAS  Google Scholar 

  24. Casanova ML, Blazquez C, Martinez-Palacio J, Villanueva C, Fernandez-Acenero MJ, Huffman JW et al. Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. J Clin Invest 2003; 111: 43–50.

    Article  CAS  Google Scholar 

  25. Sarfaraz S, Afaq F, Adhami VM, Mukhtar H . Cannabinoid receptor as a novel target for the treatment of prostate cancer. Cancer Res 2005; 65: 1635–1641.

    Article  CAS  Google Scholar 

  26. Blazquez C, Carracedo A, Barrado L, Real PJ, Fernandez-Luna JL, Velasco G et al. Cannabinoid receptors as novel targets for the treatment of melanoma. FASEB J 2006; 20: 2633–2635.

    Article  CAS  Google Scholar 

  27. Carracedo A, Gironella M, Lorente M, Garcia S, Guzman M, Velasco G et al. Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. Cancer Res 2006; 66: 6748–6755.

    Article  CAS  Google Scholar 

  28. McKallip RJ, Lombard C, Fisher M, Martin BR, Ryu S, Grant S et al. Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease. Blood 2002; 100: 627–634.

    Article  CAS  Google Scholar 

  29. Aguado T, Carracedo A, Julien B, Velasco G, Milman G, Mechoulam R et al. Cannabinoids induce glioma stem-like cell differentiation and inhibit gliomagenesis. J Biol Chem 2007; 282: 6854–6862.

    Article  CAS  Google Scholar 

  30. Xu X, Liu Y, Huang S, Liu G, Xie C, Zhou J et al. Overexpression of cannabinoid receptors CB1 and CB2 correlates with improved prognosis of patients with hepatocellular carcinoma. Cancer Genet Cytogenet 2006; 171: 31–38.

    Article  CAS  Google Scholar 

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Acknowledgements

This research project was supported by a grant from King Abdulaziz City for Science and Technology (ARP-24-11). We thank Dr Raafat M El-Sayed from Animal Facility for his excellent support.

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Correspondence to Y Shi.

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Shi, Y., Zou, M., Baitei, E. et al. Cannabinoid 2 receptor induction by IL-12 and its potential as a therapeutic target for the treatment of anaplastic thyroid carcinoma. Cancer Gene Ther 15, 101–107 (2008). https://doi.org/10.1038/sj.cgt.7701101

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  • DOI: https://doi.org/10.1038/sj.cgt.7701101

Keywords

  • interleukin-12
  • gene therapy
  • anaplastic thyroid carcinoma
  • cannabinoid
  • CB2 receptor

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