Induction of thyroid papillary carcinoma cell proliferation by estrogen is associated with an altered expression of Bcl-xL.

PURPOSE: One of the features of thyroid carcinoma is its predilection for women of reproductive age relative to men. An increased risk has also been documented in women who have used estrogens for gynecologic reasons. The aim of this study was to explore the mechanism by which sex hormones contribute to the development of thyroid carcinoma, which is not well understood at present. MATERIALS AND METHODS: In this study, we investigated the effects of estradiol and testosterone on cell proliferation in a human thyroid papillary carcinoma cell line (KAT5) by MTT assay. We also studied the expression of estrogen receptors and the levels of anti-apoptotic Bcl-xL protein, pro-apoptotic Bax protein, and messenger RNA in the cells by Western blot and reverse transcriptase polymerase chain reaction analysis. RESULTS: The results showed that estradiol promotes cell proliferation when compared with cells treated with testosterone and untreated cells, and that the growth-promoting effect of estradiol was attenuated by tamoxifen. The expression of Bcl-xL was markedly increased in a dose-dependent manner, resulting in an elevated ratio of Bcl-xL to Bax. DISCUSSION: We conclude that estradiol promotes KAT5 cell proliferation and that the underlying mechanism may be associated with up-regulation of Bcl-xL expression. The data provide insight into the molecular mechanism underlying the epidemiologic data that shows a two- to threefold increased prevalence of thyroid carcinoma in women relative to men. From the therapeutic point of view, the finding that estradiol enhances anti-apoptotic signaling pathways may be significant in the search for novel prevention and treatment strategies of thyroid carcinomas.

Heme oxygenase-1 protects against apoptosis induced by tumor necrosis factor-alpha and cycloheximide in papillary thyroid carcinoma cells.

Heme oxygenase-1 (HO-1) plays a role in the resistance to apoptosis of several types of cells, but its role in the development of thyroid cancer is unknown. In this study, we investigated the regulation of HO-1 in human papillary thyroid carcinoma cells (KAT5). The results show that HO-1 is significantly induced by hemin and cadmium. In addition to inducing HO-1, hemin and cadmium also cause a rise in the levels of p21, a cyclin-dependent kinase inhibitor. Cells with increased levels of HO-1 and p21 were more resistant to apoptotic stimuli than cells with normal levels. The cells resistant to apoptosis also displayed an increased arrest at the G(0)/G(1) phase of the cell-cycle. The induced levels of HO-1 and p21 were significantly reduced by p38 mitogen-activated protein kinase (p38 MAPK) and extracellular-regulated kinase (ERK) inhibitors. More importantly, KAT5 cells regained their sensitivity to apoptotic stimuli after they were treated with these kinase inhibitors, indicating that p38 MAPK and ERK are required for the resistance to apoptosis conferred by HO-1. Furthermore, we demonstrated that increased levels of HO-1 and p21 expression are associated with an increase in the activity of NF-kappaB and that inhibiting NF-kappaB leads to a block in the induction of HO-1 and p21. In summary, this study reveals that an increase in the level of HO-1 markedly reduces the sensitivity of papillary thyroid carcinoma cells to apoptotic stimuli. The HO-1 pathway of apoptosis resistance is associated with an increase in the levels of p21, involves a p38 MAPK and ERK-mediated mechanism and can be suppressed by inhibiting NF-kappaB.