Follicular-derived thyroid cancers are usually sensitive to conventional therapy. The prognosis of most patients with differentiated thyroid cancer is very good (6
), and most patients survive long disease-free intervals after appropriate thyroid surgery, and when necessary, radioiodine I131
). Unfortunately this is not true of 30% of the cases, which develop toward dedifferentiation. The dedifferentiation process can lead to poorly differentiated thyroid cancer cells, which undergo a reduction in or disappearance of thyroid stimulating hormone (TSH) receptor and thyroglobulin expression, and therefore lose their ability to capture iodine. Lack of radioiodine uptake in thyroid cancer is usually associated with increased growth rate and larger tumor load and is seen in approximately 50% of patients with distant metastases (31
). The ability to capture iodine is clinically important since it is associated with to the tumor’s sensitivity to radioiodine therapy. In many patients with identifiable I131
-negative lesions, surgery and radiotherapy may not be feasible owing to inoperability, previous radiotherapy, or additional distant metastases. Meanwhile, conventional chemotherapy is often ineffective. Thus, alternative treatment options are needed.
Notch1 is a multifunctional transmembrane receptor that regulates cellular differentiation, development, proliferation, and survival in a variety of contexts. However, the role of Notch1 in cancer cells remains controversial. Recent studies demonstrate that Notch1 signaling can act as either a tumor suppressor or as a tumor promoter, transient expression of active Notch1 in small cell lung cancer, pancreatic carcinoid, and prostate cancer cells inhibits cell growth in vitro ( see review in reference (12
)). We have shown that stable expression of Notch1 (NICD) in pancreatic carcinoid BON and TT cells (16
) leads to growth inhibition and reduction in neuroendocrine hormone production. However, the role of Notch1 signaling in follicular-derived thyroid cancer cells has, until now, not been described.
In this study, we have shown that active Notch1 (NICD) is minimal in thyroid cancer cells. NICD induction by VPA and SBHA led to dose responsive increase in functional Notch1 protein production as measured by western blot and CBF1 binding studies, resulting in activation of the Notch1 pathway. Furthermore, continuous Notch1 activation in thyroid cancer cells inhibited tumor cell growth. Notably, this growth reduction was dependent on the levels of Notch1 protein present. RNA interference experiments confirmed that these effects of VPA and SBHA on cell proliferation are mediated by Notch1 signaling. Our findings provide the first documentation of the role of Notch1 signaling as a tumor suppressor in thyroid cancer cells.
Moreover, the findings of this study suggest that the strong inhibition of thyroid cancer cells growth by Notch1 activation may be due to alterations in cell cycle related gene expression. p21 is a universal inhibitor of cyclin-dependent kinases. The observations of up-regulation of p21 and down-regulation of cyclin D1 following the activation of Notch1 suggest that growth inhibition of FTC cells may be due to cell cycle arrest.
Histone deacetylase (HDAC) inhibitors comprise a diverse group of structurally heterogeneous compound that exert antineoplastic effects in a variety of cancers in vitro and in vivo including multiple myeloma, lymphoid cancer, malignant glioma, neuroblastoma, cervical and ovarian cancer, and melanoma. VPA or SBHA has been shown, by our group, to inhibit a variety of NETs, including medullary thyroid cancer (19
), gastrointestinal and lung carcinoid cancer (17
) through the induction of Notch1. To our knowledge, this paper is the first report indicating the activation of Notch1 by HDAC inhibitors and cell growth suppression in follicular-derived thyroid cancer cells. Based on these findings, a clinical trial will be initiated at our institution to evaluate the effectiveness of activating Notch1 signaling by HDAC inhibitors for the treatment of patients with advanced and poorly differentiated thyroid cancer.