Thyroid Cancer Proliferation Research Articles

Utility of a Histone Deacetylase Inhibitor (PXD101) for Thyroid Cancer Treatment

BackgroundWe evaluated the therapeutic effects of the histone deacetylase inhibitor PXD101 alone and in combination with conventional chemotherapy in treating thyroid cancer.Methodology/Principal FindingsWe studied eight cell lines from four types of thyroid cancer (papillary, follicular, anaplastic and medullary). The cytotoxicity of PXD101 alone and in combination with three conventional chemotherapeutic agents (doxorubicin, paclitaxel and docetaxel) was measured using LDH assay. Western blot assessed expression of acetylation of histone H3, histone H4 and tubulin, proteins associated with apoptosis, RAS/RAF/ERK and PI3K/AKT/mTOR signaling pathways, DNA damage and repair. Apoptosis and intracellular reactive oxygen species (ROS) were measured by flow cytometry. Mice bearing flank anaplastic thyroid cancers (ATC) were daily treated with intraperitoneal injection of PXD101 for 5 days per week. PXD101 effectively inhibited thyroid cancer cell proliferation in a dose-dependent manner. PXD101 induced ROS accumulation and inhibited RAS/RAF/ERK and PI3K/mTOR pathways in sensitive cells. Double-stranded DNA damage and apoptosis were induced by PXD101 in both sensitive and resistant cell lines. PXD101 retarded growth of 8505C ATC xenograft tumors with promising safety. Combination therapy of PXD101with doxorubicin and paclitaxel demonstrated synergistic effects against four ATC lines in vitro.ConclusionsPXD101 represses thyroid cancer proliferation and has synergistic effects in combination with doxorubicin and paclitaxel in treating ATC. These findings support clinical trials using PXD101 for patients with this dismal disease.

Notch Pathway Is Activated by MAPK Signaling and Influences Papillary Thyroid Cancer Proliferation

Mutually exclusive genetic alterations in the RET, RAS, or BRAF genes, which result in constitutively active mitogen-activated protein kinase (MAPK) signaling, are present in about 70% of papillary thyroid carcinomas (PTCs). However, the effect of MAPK activation on other signaling pathways involved in oncogenic transformation, such as Notch, remains unclear. In this study, we tested the hypothesis that the MAPK pathway regulates Notch signaling and that Notch signaling plays a role in PTC cell proliferation. Conditional induction of MAPK signaling oncogenes RET/PTC3 or BRAFT1799A in normal rat thyroid cell line mediated activation of Notch signaling, upregulating Notch1 receptor and Hes1, the downstream effector of Notch pathway. Conversely, pharmacological inhibition of MAPK reduced Notch signaling in PTC cell. Thyroid tumor samples from transgenic mice expressing BRAFT1799A and primary human PTC samples showed high levels of Notch1 expression. Down-regulation of Notch signaling by γ-secretase inhibitor (GSI) or NOTCH1 RNA interference reduces PTC cell proliferation. Moreover, the combination of GSI with a MAPK inhibitor enhanced the growth suppression in PTC cells. This study revealed that RET/PTC and BRAFT1799A activate Notch signaling and promote tumor growth in thyroid follicular cell. Taken together, these data suggest that Notch signaling may be explored as an adjuvant therapy for thyroid papillary cancer.

Utility of a PI3K/mTOR Inhibitor (NVP-BEZ235) for Thyroid Cancer Therapy

BackgroundWe assessed the utility of the dual PI3K/mTOR inhibitor NVP-BEZ235 (BEZ235) as single agent therapy and in combination with conventional chemotherapy for thyroid cancer.Methodology/Principal FindingsEight cell lines from four types of thyroid cancer (papillary, follicular, anaplastic, medullary) were studied. The cytotoxicity of BEZ235 and five conventional chemotherapeutic agents alone and in combination was measured using LDH assay. Quantitative western blot assessed expression of proteins associated with cell cycle, apoptosis and signaling pathways. Cell cycle distribution and apoptosis were measured by flow cytometry. Murine flank anaplastic thyroid cancers (ATC) were treated with oral BEZ235 daily. We found that BEZ235 effectively inhibited cell proliferation of all cancer lines, with ATC exhibiting the greatest sensitivity. BEZ235 consistently inactivated signaling downstream of mTORC1. BEZ235 generally induced cell cycle arrest at G0/G1 phase, and also caused apoptosis in the most sensitive cell lines. Baseline levels of p-S6 ribosomal protein (Ser235/236) and p27 correlated with BEZ235 sensitivity. Growth of 8505C ATC xenograft tumors was inhibited with BEZ235, without any observed toxicity. Combination therapy of BEZ235 and paclitaxel consistently demonstrated synergistic effects against ATC in vitro.ConclusionsBEZ235 as a single therapeutic agent inhibits thyroid cancer proliferation and has synergistic effects in combination with paclitaxel in treating ATC. These findings encourage future clinical trials using BEZ235 for patients with this fatal disease.

Oestrogen mediates the growth of human thyroid carcinoma cells via an oestrogen receptor – ERK pathway

Although thyroid cancer occurs much more frequently in females, the role of sex hormones in thyroid carcinogenesis is unknown. In this study, it has been investigated how 17beta-oestradiol (E2) influenced proliferation and growth of thyroid cancer cells. Cell proliferation and its related molecules were examined in thyroid papillary carcinoma cells (KAT5), follicular thyroid carcinoma cells (FRO) and anaplastic carcinoma cells (ARO). Levels of oestrogen receptor (ER) alpha and beta were regulated by their agonists (PPT and DPN), antagonists and siRNA. E2 promoted cell proliferation. Such an effect was positively related to ERalpha but negatively to ERbeta; PPT enhanced cell proliferation while DPN inhibited it. PPT increased Bcl-2 expression while DPN decreased it. DPN also elevated Bax expression. PPT elevated the level of phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), suggesting a positive role of ERK1/2 in E2-induced cell proliferation. Knockdown of ERalpha significantly attenuated E2-mediated Bcl-2 and pERK1/2 expression. In contrast, knockdown of ERbeta markedly enhanced them. Oestrogen stimulates proliferation of thyroid cancer cells, associated with increase in Bcl-2 and decrease in Bax levels in an ERK1/2-related pathway. Imbalance between ERalpha and ERbeta may contribute to thyroid carcinogenesis.

FLIPping the Balance between Apoptosis and Proliferation in Thyroid Cancer

In an article in this issue of Clinical Cancer Research , Mitsiades et al. ([1][1]) suggest that molecular alterations in thyroid cancer can divert a death receptor–mediated apoptotic pathway into a proliferative response, which poses a serious challenge to treating this cancer effectively by