Future Prospects for the Treatment of Graves' Hyperthyroidism and Eye Disease.

Although there are adequate therapies for Graves' hyperthyroidism, mild to moderate Graves' orbitopathy (GO) is usually treated symptomatically whereas definitive therapy is reserved for severe, vision-threatening GO. Importantly, none of the treatment regimens for Graves' disease used today are directed at the pathogenesis of the disease. Herein, we review some aspects of what is known about the pathogenesis of these 2 major components of Graves' disease, specifically the apparent important roles of the TSH and IGF-1 receptors, and thereafter describe future therapeutic approaches directed at these receptors. We propose that targeting these receptors will yield effective and better tolerated treatments for Graves' disease, especially for GO.

miR-449a targets HDAC-1 and induces growth arrest in prostate cancer.

Histone deacetylases (HDACs) are frequently overexpressed in broad range of cancer types, where they alter cellular epigenetic programming to promote cell proliferation and survival. However, the mechanism by which HDACs become overexpressed in human cancers remains somewhat of a mystery. In this study, we investigated the expression and functional significance of miR-449a in prostate cancer cells. Using real-time PCR, we found that miR-449a is downregulated in prostate cancer tissues relative to patient-matched control tissue. Introduction of miR-449a into PC-3 prostate cancer cells resulted in cell-cycle arrest, apoptosis and a senescent-like phenotype. In silico analysis of 3'-UTR regions identified a number of genes involved in cell-cycle regulation as putative targets of miR-449a. Using a luciferase 3'-UTR reporter system, we established that HDAC-1 (histone deacetylase 1), a gene that is frequently overexpressed in many types of cancer, is a direct target of miR-449a. Further, our data indicate that miR-449a regulates cell growth and viability in part by repressing the expression of HDAC-1 in prostate cancer cells. Our findings provide new insight into the function of miRNA in regulating HDAC expression in normal versus cancerous tissue.

Knockdown of astrocyte-elevated gene-1 inhibits prostate cancer progression through upregulation of FOXO3a activity.

Astrocyte-elevated gene-1 (AEG-1) has been reported to be upregulated in several malignancies and play a critical role in Ha-ras-mediated oncogenesis through the phosphatidylinositol 3-kinase/AKT signaling pathway. However, the role of AEG-1 in prostate cancer (PC) has never been reported. We now show that AEG-1 is overexpressed in clinical PC tissue samples and cultured PC cells compared to benign prostatic hyperplasia tissue samples and normal prostate epithelial cells. Interestingly, AEG-1 knockdown induced cell apoptosis through upregulation of forkhead box (FOXO) 3a activity. This alteration of FOXO3a activity was dependent on reduction of AKT activity in LNCaP and PC-3 cells with high constitutive AKT activity, but not in DU145 cells with low constitutive AKT activity, although AEG-1 knockdown had no impact on phosphatase and tensin homolog expression in these cells. AEG-1 knockdown also attenuated the constitutive activity of the nuclear factor kappaB (NF-kappaB) and the activator protein 1 (AP-1) with a corresponding depletion in the expression of NF-kappaB and AP-1-regulated genes (interleukin (IL)-6, IL-8 and matrix metalloproteinase-9) and significantly decreased cell invasion properties of PC-3 and DU145 cells. Overall, our findings suggest that aberrant AEG-1 expression plays a dominant role as a positive auto-feedback activator of AKT and as a suppressor of FOXO3a in PC cells. AEG-1 may therefore represent a novel genetic biomarker to serve as an attractive molecular target for new anticancer agents to prevent PC cell progression and metastasis.

Cytokine-induced stabilization of newly synthesized I(kappa)B-alpha.

NF-kappaB activation is triggered by the degradation of inhibitory proteins, such as I(kappa)B-alpha. I(kappa)B-alpha levels are only transiently lowered since one gene activated by NF-kappaB is I(kappa)B-alpha. We found that I(kappa)B-alpha was replenished rapidly in a human colon cell line (HT-29), even in the presence of degradation-inducing phosphorylation (at serine-32). This finding lead us to hypothesize that posttranscriptional mechanisms were also in place to facilitate I(kappa)B-alpha replenishment. Expression of I(kappa)B-alpha from the constitutive, non-NF-kappaB regulated cytomegalovirus promoter in HT-29 cells showed that TNF-alpha or IL-1beta treatment increased I(kappa)B-alpha levels in the absence of transcriptional activation. The TNF-alpha-induced increase in transgenic I(kappa)B-alpha appeared to result from the stabilization of newly synthesized I(kappa)B-alpha, since this increase was effectively preempted by a proteasome inhibitor (MG132) or by I(kappa)B-alpha stabilization through the deletion C-terminal destabilizing elements (without additive or synergistic effects). Analysis of a hepatoma cell line (Hepa 1-4C7) indicated that the I(kappa)B-alpha stabilization may be constitutive in these cells. NF-kappaB stimuli therefore appear to trigger negative feedback pathways in some cells that terminate a NF-kappaB response by increasing the stability of newly synthesized I(kappa)B-alpha.