The BRAFV600E mutation is closely linked to tumorigenesis and malignant phenotype of papillary thyroid cancer. Signaling pathways activated by BRAFV600E are still unclear except a common activation pathway, MAPK cascade. To investigate the possible target of BRAFV600E, we developed two different cell culture models: 1) doxycycline-inducible BRAFV600E-expressing clonal line derived from human thyroid cancer WRO cells originally harboring wild-type BRAF; 2) WRO, KTC-3, and NPA cells infected with an adenovirus vector carrying BRAFV600E. BRAFV600E expression induced ERK phosphorylation and cyclin D1 expression in these cells. The BRAFV600E-overexpressing cells also showed an increase of nuclear factor kappaB (NF-kappaB) DNA-binding activity, resulting in up-regulation of antiapoptotic c-IAP-1, c-IAP-2, and X-linked inhibitor of apoptosis. Furthermore, BRAFV600E expression also induced the expression of matrix metalloproteinase and cell invasion into matrigel through NF-kappaB pathway. Increased invasive ability by BRAFV600E expression was significantly inhibited by a specific NF-kappaB inhibitor, racemic dehydroxymethylepoxyquinomicin. These data indicate that BRAFV600E activates not only MAPK but also NF-kappaB signaling pathway in human thyroid cancer cells, leading to an acquisition of apoptotic resistance and promotion of invasion. Inactivation of NF-kappaB may provide a new therapeutic modality for thyroid cancers with BRAFV600E.

Gleevec, a selective tyrosine kinase inhibitor, retarded the growth of anaplastic thyroid cancer cell lines in vitro and in vivo through selective inhibition of ABL tyrosine kinase activity. In the present study, we investigated the ability of Gleevec to modulate the in vitro and in vivo radiation response of anaplastic thyroid cancer cells. Cell growth assays, colony formation assays and xenograft models were used to quantify the radiosensitizing effect of Gleevec in cells of the anaplastic thyroid cancer cell lines ARO and FRO. FACS, Western blotting and histochemical techniques were employed to study the mechanisms of radiation response after exposure to Gleevec. Gleevec (7.0 microM) increased the anti-proliferative effect of radiation on the growth ARO and FRO cells in vitro. Clonogenic analysis demonstrated that Gleevec reduced cell survival after irradiation. Gleevec combined with radiation produced an increase in tumor growth inhibition compared to treatment with either modality alone in mice bearing anaplastic thyroid cancer xenografts. The drug suppressed radiation-induced ABL activation and promoted CDKN1A (p21(cip1)) accumulation in irradiated anaplastic thyroid cancer cells. Gleevec had an additional effect on radiation-induced apoptosis in cells of both cell lines and potentiated the induction of terminal growth arrest accompanied by the expression of senescence-associated beta-galactosidase. The antitumor effect of Gleevec is potentiated in adjunctive therapy with radiation not only due to inhibition of proliferative cell growth with transient cell cycle arrest and apoptosis, but also due to the terminal growth arrest associated with senescence, suggesting that tumor cell senescence is a mechanism for tumor targeting therapy in combination with ionizing radiation.

JNK signaling is an essential component of ATC cell proliferation and survival after radiation therapy. Hence, pharmacological interference with JNK pathway in combination with radiotherapy may be a promising treatment of ATC.

PurposeThe purpose of this paper is to compare and contrast the corporate governance standards of Cyprus, Russia, and Kazakhstan to those of the UK to facilitate investment decisions. The paper aims to discover governance gaps creating a potential for alignment to UK standards.Design/methodology/approachThe paper is a qualitative case study of four countries based on the OECD criteria of 118 corporate governance measures.FindingsThe findings indicate that the corporate governance standards in Cyprus match 92 per cent of the UK standards, Russian standards match 75 per cent, and Kazakhstan ones 63 per cent. The greatest contrast to the UK standards were for Cyprus in the area of disclosure and transparency category, Russia's was in the area of responsibilities of the board, and Kazakhstan's was highest in the two areas mentioned above and low overall.Research limitations/implicationsThe paper identifies areas of governance that could be aligned to UK standards. Further research is needed to compare the governance standards of the countries studied to international standards other than those of the UK's.Practical implicationsThe paper provides insight on governance for investors in the three countries and aids effective investment decisions.Social implicationsThe paper identifies areas of governance needing regulatory adjustment in the three countries and could influence government and industry policy.Originality/valueThe originality of the paper lies in identifying gaps in governance among the four countries. Thus the paper provides information for investors as to the corporate governance they are likely to experience, and facilitates development in governance regulation.