Protein arginine methyltransferase 5 (PRMT5) regulates gene expression either transcriptionally by symmetric dimethylation of arginine residues on histones H4R3, H3R8, and H2AR3 or at the posttranslational level by methylation of nonhistone target proteins. Although emerging evidence suggests that PRMT5 functions as an oncogene, its role in metabolic diseases is not well-defined. We investigated the role of PRMT5 in promoting high-fat-induced hepatic steatosis. A high-fat diet up-regulated PRMT5 levels in the liver but not in other metabolically relevant tissues such as skeletal muscle or white and brown adipose tissue. This was associated with repression of master transcription regulators involved in mitochondrial biogenesis. In contrast, lentiviral short hairpin RNA-mediated reduction of PRMT5 significantly decreased phosphatidylinositol 3-kinase/AKT signaling in mouse AML12 liver cells. PRMT5 knockdown or knockout decreased basal AKT phosphorylation but boosted the expression of peroxisome proliferator-activated receptor α (PPARα) and PGC-1α with a concomitant increase in mitochondrial biogenesis. Moreover, by overexpressing an exogenous WT or enzyme-dead mutant PRMT5 or by inhibiting PRMT5 enzymatic activity with a small-molecule inhibitor, we demonstrated that the enzymatic activity of PRMT5 is required for regulation of PPARα and PGC-1α expression and mitochondrial biogenesis. Our results suggest that targeting PRMT5 may have therapeutic potential for the treatment of fatty liver.

ObjectiveAssociation between prostate cancer and obesity remains controversial. Allelic deletions of PTEN, a tumor suppressor gene, are common in prostate cancer in men. Monoallelic Pten deletion in mice causes low prostatic intraepithelial neoplasia (mPIN). This study tested the effect of a hypercaloric diet on prostate cancer in Pten+/− mice.Methods1-month old mice were fed a high-calorie diet deriving 45% calories from fat for 3 and 6 months before prostate was analyzed histologically and biochemically for mPIN progression. Because Pten+/− mice are protected against diet-induced insulin resistance, we tested the role of insulin on cell growth in RWPE-1 normal human prostatic epithelial cells with siRNA knockdown of PTEN.ResultsIn addition to activating PI3 kinase/Akt and Ras/MAPkinase pathways, high-calorie diet causes neoplastic progression, angiogenesis, inflammation and epithelial–mesenchymal transition. It also elevates the expression of fatty acid synthase (FAS), a lipogenic gene commonly elevated in progressive cancer. SiRNA-mediated downregulation of PTEN demonstrates increased cell growth and motility, and soft agar clonicity in addition to elevation in FAS in response to insulin in RWPE-1 normal human prostatic cells. Downregulating FAS in addition to PTEN, blunted the proliferative effect of insulin (and IL-6) in RWPE-1 cells.ConclusionHigh-calorie diet promotes prostate cancer progression in the genetically susceptible Pten haploinsufficient mouse while preserving insulin sensitivity. This appears to be partly due to increased inflammatory response to high-caloric intake in addition to increased ability of insulin to promote lipogenesis.

The use of oral antineoplastic agents in nonmedical settings continues to increase. There are limited data available on pediatric exposures to these agents. We sought to identify characteristics of such exposures. We performed a retrospective review of database of a statewide poison system from 2000 to 2009 for all cases of pediatric exposures to oral antineoplastic agents, which took place in a nonmedical setting. Data collected include gender, age, agent of exposure, dose, drug concentration, reason for exposure, symptoms, outcomes, interventions, and length of hospital stay. There were a total of 328 patients. The mean average age was 4.1 years. Eighty-nine percentage (n = 293) was unintentional. Exposures to 21 different antineoplastic agents were identified. Methotrexate (n = 91) and 6-mercaptopurine (n = 47) were the most common agents encountered. Two hundred ninety-nine (91%) cases had no symptoms reported. When reported, gastrointestinal symptoms (n = 17) and central nervous system sedation (n = 6) were most common. One case of pancytopenia was reported. No deaths were reported in this series. Sixty-seven percent (n = 220) were managed at home, whereas 19 (6%) were admitted to a health care facility. Cases were followed by the poison control center for 0.34 days (SD = 1.40). In this study, exposures to oral antineoplastics were primarily unintentional, asymptomatic, and managed at home. Study limitations include possible reporting bias, inability to objectively confirm exposures, and limited duration of monitoring by the poison control center. In this retrospective review, no significant morbidity or mortality was reported from pediatric exposures to oral antineoplastic drugs in the nonmedical setting.

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