Biliverdin Reductase A Attenuates Hepatic Steatosis by Inhibition of Glycogen Synthase Kinase (GSK) 3ß Phosphorylation of Serine 73 of Peroxisome Proliferator-activated Receptor (PPAR) α.

Non-alcoholic fatty liver disease is the most rapidly growing form of liver disease and if left untreated can result in non-alcoholic steatohepatitis, ultimately resulting in liver cirrhosis and failure. Biliverdin reductase A (BVRA) is a multifunctioning protein primarily responsible for the reduction of biliverdin to bilirubin. Also, BVRA functions as a kinase and transcription factor, regulating several cellular functions. We report here that liver BVRA protects against hepatic steatosis by inhibiting glycogen synthase kinase 3ß (GSK3ß) by enhancing serine 9 phosphorylation, which inhibits its activity. We show that GSK3ß phosphorylates serine 73 (Ser(P)73) of the peroxisome proliferator-activated receptor α (PPARα), which in turn increased ubiquitination and protein turnover, as well as decreased activity. Interestingly, liver-specific BVRA KO mice had increased GSK3ß activity and Ser(P)73 of PPARα, which resulted in decreased PPARα protein and activity. Furthermore, the liver-specific BVRA KO mice exhibited increased plasma glucose and insulin levels and decreased glycogen storage, which may be due to the manifestation of hepatic steatosis observed in the mice. These findings reveal a novel BVRA-GSKß-PPARα axis that regulates hepatic lipid metabolism and may provide unique targets for the treatment of non-alcoholic fatty liver disease.

Deciphering the Roles of Thiazolidinediones and PPARγ in Bladder Cancer.

The use of thiazolidinedione (TZD) therapy in type II diabetic patients has proven useful in the lowering of blood glucose levels. However, recent investigations have shown that there may be potential health concerns associated, including the risk of developing bladder cancer as well as complications in the cardiovasculature. TZDs are ligands for the nuclear receptor PPARγ, and activation causes lipid uptake and insulin sensitization, both of which are critical processes for diabetic patients whose bodies are unable to utilize insulin effectively. Several studies have shown that PPARγ/TZDs decrease IGF-1 levels and, thus, reduce cancer growth in carcinomas such as the pancreas, colon, liver, and prostate. However, other studies have shed light on the potential of the receptor as a biomarker for uroepithelial carcinomas, particularly due to its stimulatory effect on migration of bladder cancer cells. Furthermore, PPARγ may provide the tumor-promoting microenvironment by de novo synthesis of nutrients that are needed for bladder cancer development. In this review, we closely examine the TZD class of drugs and their effects on PPARγ in patient studies along with additional molecular factors that are positive modulators, such as protein phosphatase 5 (PP5), which may have considerable implications for bladder cancer therapy.

Prostate Cancer in African American Men: The Effect of Androgens and microRNAs on Epidermal Growth Factor Signaling.

Prostate cancer (PC) is one of the leading causes of mortality amongst elderly men in the USA and is second only to lung cancer. African Americans (AA) are at an increased risk of developing PC and are more likely to die from the disease in comparison to Caucasian Americans (CA). Chromosomal alterations or genetic differences between AA and CA may account for the variances observed in PC progression. Importantly, mutations in the androgen receptor (AR) or the epidermal growth factor receptor (EGFR) may contribute to the disparity. Current studies are investigating the role of small nucleotide polymorphisms (SNPs) and microRNAs (miRNAs), which affect protein translation of the receptors by regulation of the 3' untranslated region (UTR), which may enhance the progression of PC. However, these genetic differences have not been fully explored in prostates between the two ethnic groups. This review will highlight the current studies on the EGFR signaling pathway as well as the involvement of SNPs and miRNAs and relate them to variances observed in PC of AA and CA men. With an understanding of these differences, specific preventive and therapeutic strategies may be developed to target personalized medicine for prostate carcinogenesis.

Sweet-P inhibition of glucocorticoid receptor ß as a potential cancer therapy.

The need for the development of new cancer therapies and push for the design of new targeting techniques is on the rise, and would be useful for cancers that are resistant to current drug treatments. The understanding of the genome has significantly advanced cancer therapy, as well as prevention and earlier detection. This research highlight discusses a potential new type of cancer-targeting molecule, Sweet-P, which is the first of its kind. Sweet-P specifically targets the microRNA-144 binding site in the 3' untranslated region (3' UTR) of the human glucocorticoid receptor ß (GRß), which has been demonstrated to increase expression. GRß has been shown to be highly expressed in cells from solid tumors of uroepithelial carcinomas, gliomas, osteosarcomas, and hepatocellular carcinomas, as well as in liquid tumor cells from leukemia patients. In non-cancerous diseases, GRß has been shown to be highly expressed in glucocorticoid-resistant asthma. These maladies brought the need for the development of the Sweet-P anti-GRß molecule. Sweet-P was shown to repress the migration of bladder cancer cells, and may serve as a new therapeutic for GRß-related diseases.

Glucocorticoid receptor beta increases migration of human bladder cancer cells.

Bladder cancer is observed worldwide having been associated with a host of environmental and lifestyle risk factors. Recent investigations on anti-inflammatory glucocorticoid signaling point to a pathway that may impact bladder cancer. Here we show an inverse effect on the glucocorticoid receptor (GR) isoform signaling that may lead to bladder cancer. We found similar GRα expression levels in the transitional uroepithelial cancer cell lines T24 and UMUC-3. However, the T24 cells showed a significant (p < 0.05) increased expression of GRß compared to UMUC-3, which also correlated with higher migration rates. Knockdown of GRß in the T24 cells resulted in a decreased migration rate. Mutational analysis of the 3' untranslated region (UTR) of human GRß revealed that miR144 might positively regulate expression. Indeed, overexpression of miR144 increased GRß by 3.8 fold. In addition, miR144 and GRß were upregulated during migration. We used a peptide nucleic acid conjugated to a cell penetrating-peptide (Sweet-P) to block the binding site for miR144 in the 3'UTR of GRß. Sweet-P effectively prevented miR144 actions and decreased GRß expression, as well as the migration of the T24 human bladder cancer cells. Therefore, GRß may have a significant role in bladder cancer, and possibly serve as a therapeutic target for the disease.

Timcodar (VX-853) Is a Non-FKBP12 Binding Macrolide Derivative That Inhibits PPARγ and Suppresses Adipogenesis.

Nutrient overload and genetic factors have led to a worldwide epidemic of obesity that is the underlying cause of diabetes, atherosclerosis, and cardiovascular disease. In this study, we used macrolide drugs such as FK506, rapamycin, and macrolide derived, timcodar (VX-853), to determine their effects on lipid accumulation during adipogenesis. Rapamycin and FK506 bind to FK506-binding proteins (FKBPs), such as FKBP12, which causes suppression of the immune system and inhibition of mTOR. Rapamycin has been previously reported to inhibit the adipogenic process and lipid accumulation. However, rapamycin treatment in rodents caused immune suppression and glucose resistance, even though the mice lost weight. Here we show that timcodar (1 µM), a non-FKBP12-binding drug, significantly (p < 0.001) inhibited lipid accumulation during adipogenesis. A comparison of the same concentration of timcodar (1 µM) and rapamycin (1 µM) showed that both are inhibitors of lipid accumulation during adipogenesis. Importantly, timcodar potently (p < 0.01) suppressed transcriptional regulators of adipogenesis, PPARγ and C/EBPα, resulting in the inhibition of genes involved in lipid accumulation. These studies set the stage for timcodar as a possible antiobesity therapy, which is rapidly emerging as a pandemic.

Involvement of the Androgen and Glucocorticoid Receptors in Bladder Cancer.

Bladder cancer is encountered worldwide having been associated with a host of environmental and lifestyle risk factors. The disease has a male to female prevalence of 3 : 1. This disparity has raised the possibility of the androgen receptor (AR) pathway being involved in the genesis of the disease; indeed, research has shown that AR is involved in and is likely a driver of bladder cancer. Similarly, an inflammatory response has been implicated as a major player in bladder carcinogenesis. Consistent with this concept, recent work on anti-inflammatory glucocorticoid signaling points to a pathway that may impact bladder cancer. The glucocorticoid receptor- (GR-) α isoform has an important role in suppressing inflammatory processes, which may be attenuated by AR in the development of bladder cancer. In addition, a GR isoform that is inhibitory to GRα, GRß, is proinflammatory and has been shown to induce cancer growth. In this paper, we review the evidence of inflammatory mediators and the relationship of AR and GR isoforms as they relate to the propensity for bladder cancer.