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Glioblastoma (GBM) is one of the most aggressive and deadly brain tumors; however, its current therapeutic strategies are limited. Selenoprotein P (SeP; SELENOP, encoded by the SELENOP gene) is a unique selenium-containing protein that exhibits high expression levels in astroglia. SeP is thought to be associated with ferroptosis sensitivity through the induction of glutathione peroxidase 4 (GPX4) via selenium supplementation. In this study, to elucidate the role of SeP in GBM, we analyzed its expression in GBM patients and found that SeP expression levels were significantly higher when compared to healthy subjects. Knock down of SeP in cultured GBM cells resulted in a decrease in GPX1 and GPX4 protein levels. Under the same conditions, cell death caused by RSL3, a ferroptosis inducer, was enhanced, however this enhancement was canceled by supplementation of selenite. These results indicate that SeP expression contributes to preserving GPX and selenium levels in an autocrine/paracrine manner, i.e., SeP regulates a dynamic cycling-selenium storage system in GBM. We also confirmed the role of SeP expression in ferroptosis sensitivity using patient-derived primary GBM cells. These findings indicate that expression of SeP in GBM can be a significant therapeutic target to overcome anticancer drug resistance. [ABSTRACT FROM AUTHOR]

Inorganic mercury is a toxic metal that accumulates in the proximal tubules of the kidney, causing apoptosis. Arginase II is known to inhibit apoptosis, but its role in the renal apoptosis caused by inorganic mercury is poorly understood. In the present study, we examined the involvement of arginase II in inorganic mercury-dependent apoptosis. A single exposure to mercuric chloride (HgCl2, 1 mg/kg) in rats resulted in a dramatic time-dependent reduction in the activity of arginase II in the kidney; for example, the activity at 48 h after exposure was 31% of the control level. The decrease in arginase II activity was due to a decrease in the protein level, not to a reduction in gene expression or to direct inhibition of the activity itself. More interestingly, diminished arginase II activity was well correlated with the induction of apoptosis as evaluated by renal DNA fragmentation ( r = 0.99). Overexpression of arginase II in LLC-PK1 cells blocked cell death during exposure to inorganic mercury. These results suggest that inorganic mercury causes a reduction in protein levels of arginase II, and that impaired arginase II activity is, at least in part, associated with the apoptotic cell damage caused by this heavy metal. [ABSTRACT FROM AUTHOR]

Ninjurin1 is a novel adhesion molecule that has a role in promoting nerve regeneration. Although ninjurin1 is ubiquitously expressed in various human tissues, including the liver, the biologic functions of ninjurin1 in tissues other than the nervous system remain unknown. The aim of this study was to investigate the function of ninjurin1 in hepatocytes.The effect of ninjurin1 overexpression was examined in Huh-7 hepatoma cells. Ninjurin1 expression was examined by Western blot in human hepatocellular carcinoma tissues as well as their adjacent liver tissues.Ninjurin1-overexpressing clones exhibited strong growth inhibition due to G1 cell cycle arrest, which is associated with a posttranscriptional increase in p21WAF1/Cip1, a decrease of cyclin-dependent kinase 2 activity and the hypophosphorylation of Rb. The ninjurin1-overexpressing clones had increased senescence-associated β-galactosidase activity and autofluorescent pigment, characteristic features of cellular senescence. The levels of ninjurin1 expression were higher in hepatocellular carcinoma tissues than those in adjacent liver tissues.The present study provides the first evidence that ninjurin1 is able to induce the senescence program. Ninjurin1 may be involved in the regulation of cellular senescence in the liver during carcinogenesis. [Copyright &y& Elsevier]

To investigate the adaptive response to the environmental electrophile methylmercury (MeHg), we performed DNA microarray analysis of human neuroblastoma SH-SY5Y cells exposed to a sub-cytotoxic dose of MeHg (1 µM) for 6 hr. The expression of 15 genes increased 10-fold or more in response to MeHg. Four of these genes are associated with detoxification and excretion of MeHg into the extracellular space, and are regulated by transcription factor Nrf2 through the electrophile response element. Interestingly, Cullin3, a negative regulator of Nrf2, was identified as a down-regulated gene during MeHg exposure. [ABSTRACT FROM AUTHOR]

Abstract: Aquaporin (AQP) 9 is a member of the aquaglyceroporin subfamily of AQPs in the transfer of water and small solutes such as glycerol and arsenite. It is well recognized that arsenic toxicity is associated with intracellular accumulation of this metalloid. In the present study, we examined the contribution of AQP9 to the uptake of inorganic arsenite, thereby increasing arsenic-induced cytotoxicity in primary mouse hepatocytes. Pretreatment with sorbitol as a competitive inhibitor of AQP9 and siRNA-mediated knockdown of AQP9 resulted in a significant decrease of arsenite uptake in the cell and its cytotoxicity. Furthermore, overexpression of AQP9 in HEK293 cells led to the enhancement of intracellular arsenic concentration, resulting in enhanced cytotoxicity after arsenite exposure. These results suggest that AQP9 is a channel to define arsenite sensitivity in primary mouse hepatocytes. [Copyright &y& Elsevier]