Oncogenic and anti-apoptotic activity of NF-kappa B in human thyroid carcinomas

Thyroid cancer includes three types of carcinomas classified as differentiated thyroid carcinomas (DTC), medullary thyroid carcinomas, and undifferentiated carcinomas (UTC). DTC and medullary thyroid carcinomas generally have a good prognosis, but UTC are usually fatal. Consequently, there is a need for new effective therapeutic modalities to improve the survival of UTC patients. Here we show that NF-kappaB is activated in human thyroid neoplasms, particularly in undifferentiated carcinomas. Thyroid cell lines, reproducing in vitro the different thyroid neoplasias, also show basal NF-kappaB activity and resistance to drug-induced apoptosis, which correlates with the level of NF-kappaB activation. Activation of NF-kappaB in the DTC cell line NPA renders these cells resistant to drug-induced apoptosis. Stable expression of a super-repressor form of IkappaBalpha (IkappaBalphaM) in the UTC cell line FRO results in enhanced sensitivity to drug-induced apoptosis, to the loss of the ability of these cells to form colonies in soft agar, and to induce tumor growth in nude mice. In addition, we show that FRO cells display a very low JNK activity that is restored in FRO-IkappaBalphaM clones. Moreover, inhibition of JNK activity renders FRO-IkappaBalphaM clones resistant to apoptosis induced by chemotherapeutic agents. Our results indicate that NF-kappaB plays a pivotal role in thyroid carcinogenesis, being required for tumor growth and for resistance to drug-induced apoptosis, the latter function very likely through the inhibition of JNK activity. Furthermore, the strong constitutive NF-kappaB activity in human anaplastic thyroid carcinomas, besides representing a novel diagnostic tool, makes NF-kappaB a target for the development of novel therapeutic strategies.