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Molecular Medicine

, Volume 18, Issue 2, pp 167–177 | Cite as

c-Met Inhibitor Synergizes with Tumor Necrosis Factor-Related Apoptosis-Induced Ligand to Induce Papillary Thyroid Carcinoma Cell Death

  • Rong Bu
  • Shahab Uddin
  • Maqbool Ahmed
  • Azhar R. Hussain
  • Saif Alsobhi
  • Tarek Amin
  • Abdurahman Al-Nuaim
  • Fouad Al-Dayel
  • Jehad Abubaker
  • Prashant Bavi
  • Khawla S. Al-Kuraya
Research Article

Abstract

The Met receptor tyrosine kinase is overexpressed and/or activated in variety of human malignancies. Previously we have shown that c-Met is overexpressed in Middle Eastern papillary thyroid carcinoma (PTC) and significantly associated with an aggressive phenotype, but its role has not been fully elucidated in PTC. The aim of this study was to determine the functional link between the c-Met/AKT signaling pathway and death receptor 5 (DR5) in a large cohort of PTC in a tissue microarray format followed by functional studies using PTC cell lines and nude mice. Our data showed that high expressions of p-Met and DR5 were significantly associated with an aggressive phenotype of PTC and correlated with BRAF mutation. Treatment of PTC cell lines with PHA665752, an inhibitor of c-Met tyrosine kinase, inhibited cell proliferation and induced apoptosis via the mitochondrial pathway in PTC cell lines. PHA665752 treatment or expression of c-Met small interfering (si)RNA resulted in dephosphorylation of c-Met, AKT and its downstream effector molecules. Furthermore, PHA665752 treatment upregulated DR5 expression via generation of reactive oxygen species in PTC cell lines, and synergistically potentiated death receptor-induced apoptosis with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Finally, cotreatment with PHA665752 and TRAIL caused more pronounced effects on PTC xenograft tumor growth in nude mice. Our data suggest that the c-Met/AKT pathway may be a potential target for therapeutic intervention for treatment of PTC refractory to conventionally therapeutic modalities.

Notes

Acknowledgments

This study was supported by King Abdulaziz City for Science and Technology (KACST) and the National Comprehensive Plan for Science and Technology (NCPST) resulting from KACST Project # 08-MED482-20. We thank V Balde, H Al Dossarie, M Sultana and KAS Al-Obaisi for their technical assistance, and S Prabhakaran and Z Qadri for data analysis.

Supplementary material

10020_2012_1802167_MOESM1_ESM.pdf (2 mb)
Supplementary material, approximately 2089 KB.

References

  1. 1.
    Nikiforov YE. (2008) Thyroid carcinoma: molecular pathways and therapeutic targets. Mod. Pathol. 21(Suppl 2):S37–43.CrossRefGoogle Scholar
  2. 2.
    Piersanti M, Ezzat S, Asa SL. (2003) Controversies in papillary microcarcinoma of the thyroid. Endocr. Pathol. 14:183–91.CrossRefGoogle Scholar
  3. 3.
    Loh KC, Greenspan FS, Gee L, Miller TR, Yeo PP. (1997) Pathological tumor-node-metastasis (pTNM) staging for papillary and follicular thyroid carcinomas: a retrospective analysis of 700 patients. J. Clin. Endocrinol. Metab. 82:3553–62.CrossRefGoogle Scholar
  4. 4.
    Hay ID. (1990) Papillary thyroid carcinoma. Endocrinol. Metab. Clin. North Am. 19:545–76.CrossRefGoogle Scholar
  5. 5.
    Siironen P, et al. (2005) Prognostic factors in papillary thyroid cancer: an evaluation of 601 consecutive patients. Tumour Biol. 26:57–64.CrossRefGoogle Scholar
  6. 6.
    Gonzatti-Haces M, et al. (1988) Characterization of the TPR-MET oncogene p65 and the MET protooncogene p140 protein-tyrosine kinases. Proc. Natl. Acad. Sci. U. S. A. 85:21–5.CrossRefGoogle Scholar
  7. 7.
    Bardelli A, Ponzetto C, Comoglio PM. (1994) Identification of functional domains in the hepatocyte growth factor and its receptor by molecular engineering. J. Biotechnol. 37:109–22.CrossRefGoogle Scholar
  8. 8.
    Lesko E, Majka M. (2008) The biological role of HGF-MET axis in tumor growth and development of metastasis. Front. Biosci. 13:1271–80.CrossRefGoogle Scholar
  9. 9.
    Desiderio MA. (2007) Hepatocyte growth factor in invasive growth of carcinomas. Cell. Mol. Life Sci. 64:1341–54.CrossRefGoogle Scholar
  10. 10.
    Tulasne D, Foveau B. (2008) The shadow of death on the MET tyrosine kinase receptor. Cell. Death Differ. 15:427–434.CrossRefGoogle Scholar
  11. 11.
    Mineo R, et al. (2004) Activation of the hepatocyte growth factor (HGF)-Met system in papillary thyroid cancer: biological effects of HGF in thyroid cancer cells depend on Met expression levels. Endocrinology. 145:4355–65.CrossRefGoogle Scholar
  12. 12.
    Ruco LP, Stoppacciaro A, Ballarini F, Prat M, Scarpino S. (2001) Met protein and hepatocyte growth factor (HGF) in papillary carcinoma of the thyroid: evidence for a pathogenetic role in tumourigenesis. J. Pathol. 194:4–8.CrossRefGoogle Scholar
  13. 13.
    Wasenius VM, Hemmer S, Kettunen E, Knuutila S, Franssila K, Joensuu H. (2003) Hepatocyte growth factor receptor, matrix metalloproteinase-11, tissue inhibitor of metalloproteinase-1, and fibronectin are up-regulated in papillary thyroid carcinoma: a cDNA and tissue microarray study. Clin. Cancer Res. 9:68–75.PubMedGoogle Scholar
  14. 14.
    Siraj AK, et al. (2007) Genome-wide expression analysis of Middle Eastern papillary thyroid cancer reveals c-MET as a novel target for cancer therapy. J. Pathol. 213:190–9.CrossRefGoogle Scholar
  15. 15.
    Bauer J, Wekerle H, Lassmann H. (1995) Apoptosis in brain-specific autoimmune disease. Curr. Opin. Immunol. 7:839–43.CrossRefGoogle Scholar
  16. 16.
    Ghobrial IM, Witzig TE, Adjei AA. (2005) Targeting apoptosis pathways in cancer therapy. C. A. Cancer J. Clin. 55:178–94.CrossRefGoogle Scholar
  17. 17.
    Bavi P, et al. (2006) Prevalence of fragile histidine triad expression in tumors from Saudi Arabia: a tissue microarray analysis. Cancer Epidemiol. Biomarkers Prev. 15:1708–18.CrossRefGoogle Scholar
  18. 18.
    Uddin S, et al. (2008) Fatty acid synthase and AKT pathway signaling in a subset of papillary thyroid cancers. J. Clin. Endocrinol. Metab. 93:4088–97.CrossRefGoogle Scholar
  19. 19.
    Uddin S, et al. (2006) Role of phosphatidylinositol 3′-kinase/AKT pathway in diffuse large B-cell lymphoma survival. Blood. 108:4178–86.CrossRefGoogle Scholar
  20. 20.
    Abubaker J, et al. (2008) Clinicopathological analysis of colorectal cancers with PIK3CA mutations in Middle Eastern population. Oncogene. 27:3539–45.CrossRefGoogle Scholar
  21. 21.
    Mandal M, et al. (2005) The Akt inhibitor KP372-1 suppresses Akt activity and cell proliferation and induces apoptosis in thyroid cancer cells. Br. J. Cancer. 92:1899–905.CrossRefGoogle Scholar
  22. 22.
    Hussain AR, et al. (2006) Curcumin induces apoptosis via inhibition of PI3′-kinase/AKT pathway in acute T cell leukemias. Apoptosis. 11:245–54.CrossRefGoogle Scholar
  23. 23.
    Uddin S, Hussain A, Al-Hussein K, Platanias LC, Bhatia KG. (2004) Inhibition of phosphatidylinositol 3′-kinase induces preferentially killing of PTEN-null T leukemias through AKT pathway. Biochem. Biophys. Res. Commun. 320:932–8.CrossRefGoogle Scholar
  24. 24.
    Hussain AR, et al. (2007) Sanguinarine-dependent induction of apoptosis in primary effusion lymphoma cells. Cancer Res. 67:3888–97.CrossRefGoogle Scholar
  25. 25.
    Uddin S, Ah-Kang J, Ulaszek J, Mahmud D, Wickrema A. (2004) Differentiation stage-specific activation of p38 mitogen-activated protein kinase isoforms in primary human erythroid cells. Proc. Natl. Acad. Sci. U. S. A. 101:147–52.CrossRefGoogle Scholar
  26. 26.
    Uddin S, et al. (2005) Inhibition of phosphatidylinositol 3′-kinase/AKT signaling promotes apoptosis of primary effusion lymphoma cells. Clin. Cancer Res. 11:3102–8.CrossRefGoogle Scholar
  27. 27.
    Christensen JG, Burrows J, Salgia R. (2005) c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett. 225:1–26.CrossRefGoogle Scholar
  28. 28.
    Tjin EP, et al. (2006) Functional analysis of HGF/MET signaling and aberrant HGF-activator expression in diffuse large B-cell lymphoma. Blood. 107:760–8.CrossRefGoogle Scholar
  29. 29.
    Bu R, et al. (2011) HGF/c-Met pathway has a prominent role in mediating antiapoptotic signals through AKT in epithelial ovarian carcinoma. Lab. Invest. 91:124–37.CrossRefGoogle Scholar
  30. 30.
    Mukohara T, et al. (2005) Inhibition of the met receptor in mesothelioma. Clin. Cancer Res. 11:8122–30.CrossRefGoogle Scholar
  31. 31.
    Samovski D, Kalderon B, Yehuda-Shnaidman E, Bar-Tana J. (2010) Gating of the mitochondrial permeability transition pore by long chain fatty acyl analogs in vivo. J. Biol. Chem. 285:6879–90.CrossRefGoogle Scholar
  32. 32.
    Chou WC, Dang CV. (2005) Acute promyelocytic leukemia: recent advances in therapy and molecular basis of response to arsenic therapies. Curr. Opin. Hematol. 12:1–6.CrossRefGoogle Scholar
  33. 33.
    Jung EM, Lim JH, Lee TJ, Park JW, Choi KS, Kwon TK. (2005) Curcumin sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through reactive oxygen species-mediated upregulation of death receptor 5 (DR5). Carcinogenesis. 26:1905–13.CrossRefGoogle Scholar
  34. 34.
    Ma PC, Maulik G, Christensen J, Salgia R. (2003) c-Met: structure, functions and potential for therapeutic inhibition. Cancer Metastasis Rev. 22:309–25.CrossRefGoogle Scholar
  35. 35.
    Furge KA, Zhang YW, Vande Woude GF. (2000) Met receptor tyrosine kinase: enhanced signaling through adapter proteins. Oncogene. 19:5582–9.CrossRefGoogle Scholar
  36. 36.
    Sawada K, et al. (2007) c-Met overexpression is a prognostic factor in ovarian cancer and an effective target for inhibition of peritoneal dissemination and invasion. Cancer Res. 67:1670–9.CrossRefGoogle Scholar
  37. 37.
    Koon EC, et al. (2008) Effect of a c-Met-specific, ATP-competitive small-molecule inhibitor SU11274 on human ovarian carcinoma cell growth, motility, and invasion. Int. J. Gynecol. Cancer. 18:976–84.CrossRefGoogle Scholar
  38. 38.
    Xiao GH, Jeffers M, Bellacosa A, Mitsuuchi Y, Vande Woude GF, Testa JR. (2001) Anti-apoptotic signaling by hepatocyte growth factor/Met via the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways. Proc. Natl. Acad. Sci. U. S. A. 98:247–52.CrossRefGoogle Scholar
  39. 39.
    Chen BK, et al. (1999) Overexpression of c-Met protein in human thyroid tumors correlated with lymph node metastasis and clinicopathologic stage. Pathol. Res. Pract. 195:427–33.CrossRefGoogle Scholar
  40. 40.
    Ramirez R, et al. (2000) Over-expression of hepatocyte growth factor/scatter factor (HGF/SF) and the HGF/SF receptor (cMET) are associated with a high risk of metastasis and recurrence for children and young adults with papillary thyroid carcinoma. Clin. Endocrinol. 53:635–44.CrossRefGoogle Scholar
  41. 41.
    Chattopadhyay C, El-Naggar AK, Williams MD, Clayman GL. (2008) Small molecule c-MET inhibitor PHA665752: effect on cell growth and motility in papillary thyroid carcinoma. Head Neck. 30:991–1000.CrossRefGoogle Scholar
  42. 42.
    Abubaker J, et al. (2008) Clinicopathological analysis of papillary thyroid cancer with PIK3CA alterations in a Middle Eastern population. J. Clin. Endocrinol. Metab. 93:611–8.CrossRefGoogle Scholar
  43. 43.
    Kumagai A, et al. (2006) No evidence of ARAF, CRAF and MET mutations in BRAFT1799A negative human papillary thyroid carcinoma. Endocr. J. 53:615–20.CrossRefGoogle Scholar
  44. 44.
    Zhang L, Fang B. (2005) Mechanisms of resistance to TRAIL-induced apoptosis in cancer. Cancer Gene. Ther. 12:228–37.CrossRefGoogle Scholar

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© The Author(s) 2012

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Authors and Affiliations

  • Rong Bu
    • 1
  • Shahab Uddin
    • 1
  • Maqbool Ahmed
    • 1
  • Azhar R. Hussain
    • 1
  • Saif Alsobhi
    • 2
  • Tarek Amin
    • 3
  • Abdurahman Al-Nuaim
    • 3
  • Fouad Al-Dayel
    • 4
  • Jehad Abubaker
    • 1
  • Prashant Bavi
    • 1
  • Khawla S. Al-Kuraya
    • 1
  1. 1.Human Cancer Genomic Research, Research CenterKing Faisal Specialist Hospital and Research Cancer, MBC#98-16RiyadhSaudi Arabia
  2. 2.Department of SurgeryKing Faisal Specialist Hospital and Research CenterRiyadhSaudi Arabia
  3. 3.Department of EndocrinologyKing Faisal Specialist Hospital and Research CenterRiyadhSaudi Arabia
  4. 4.Department of PathologyKing Faisal Specialist Hospital and Research CenterRiyadhSaudi Arabia

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