The biological behaviors of thyroid cancer are varied, and the pathological mechanisms remain unclear. Some reports indicated an apparent aggregation of amyloid accompanying medullary thyroid carcinoma (MTC). Amyloid aggregation in neurodegeneration leads to hyperactivation of Cdk5 and subsequent neuronal death. Based on the connection with amyloid, the role of Cdk5 in MTC is worthy of investigation. Initially, the expression of Cdk5 and its activator, p35, in MTC cell lines was identified. Cdk5 inhibition by specific inhibitors or short interfering RNA decreased the proliferation of MTC cell lines, which reveals the importance of Cdk5 in MTC cell growth. Although p35 cleavage has been considered as an important element in neurodegeneration, it seems that p35 cleavage was not a major cause in Cdk5 activity-dependent MTC cell proliferation because neither Cdk5 activity nor cell growth was affected by the inhibition of p35 cleavage. Clearance of amyloid by antibody neutralization indicated that MTC cell proliferation was supported by calcitonin-derived extracellular amyloid and subsequent Her2 and Cdk5 activation. Significantly, the STAT3 pathway was involved in Cdk5-dependent proliferation of MTC cells through Ser-727 phosphorylation. In addition, Cdk5 inhibition reduced nuclear distributions of both the Cdk5-p35 complex and phospho-STAT3 in MTC cells. Finally, Cdk5 inhibition retarded tumor formation in vivo accompanying the reduction of phospho-STAT3. Our findings suggest the first demonstration of a novel and specific role for Cdk5 kinase in supporting the proliferation of the medullary thyroid carcinoma cells and could shed light on a new field for diagnosis and therapy of thyroid cancer. Medullary thyroid carcinoma (MTC)2 is transformed from parafollicular C cells, which are primarily responsible for secretion of calcitonin in the thyroid gland. An abnormal increase of blood calcitonin is a common symptom for MTC (1, 2), a type of carcinoma that may be associated with MEN2 (multiple endocrine neoplasia-type 2). MEN2 occurs along with pheochromocytomas or adrenal medullary hyperplasia, in which many endocrine glands such as the thyroid, adrenals, and parathyroid are affected simultaneously in a patient. MTC has been demonstrated to be associated with amyloid fibrils aggregated in the thyroid and adjacent tissues (3). Amyloid is a self-aggregated polypeptide and tends to form insoluble fibrils that are extracellularly deposited in many protein-folding disorders such as Alzheimer disease (AD) and other amyloidoses because of overexpression, proteolytic digestion, or mutations of its precursor protein (4). In addition to typical amyloid-related diseases, type II diabetes, myocardial infarctions, and several kinds of cancers were found to be associated with amyloid aggregation. In these cases, non-neoplastic and malignant tumors of the breast, lung squamous cell carcinoma, and MTC are all associated with amyloid (5).Cdk5 (cyclin-dependent kinase 5) is a member of a small serine/threonine cyclin-dependent kinase f...

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