Gliomas are primary brain tumors that arise from differentiated glial cells through a poorly understood process of malignant transformation. Brain tumors display a complex biology because of their remarkable degree of antigenic heterogeneity, variable mutations in their genome, and their propensity for invasion into normal brain tissue. In studying gliomas obtained from patients that were diagnosed with tumors of varying degrees of malignancy, we observed the expression of a voltage-independent, amiloride-inhibitable, inward Na+ conductance that was not present in normal human glial cells or in low-grade tumors. We hypothesize that high-grade glioma cells show functional up-regulation of this characteristic Na + conductance. Glioma cell migration, cell proliferation, and cell volume regulation are all compromised if this conductance pathway is blocked with amiloride or by a peptide isolated from a spider venom. Thus, the channel membrane proteins that underlie this conductance are potentially unique, therapeutic targets. The research proposed in this application has one objective of characterizing thoroughly the ability of one subunit (ASIC2) of this amiloride-sensitive Na+ conductance pathway to traffic through the cellular biosynthetic pathway. In addition, we hypothesize that this same subunit (ASIC2) is transcriptionally regulated. Thus, in malignant brain tumors, ASIC2 either is not expressed or is retained intracellularly. There are two Specific Aims: 1) to test the hypothesis that lack of plasma membrane expression of ASIC2 in a subset of high-grade tumor cells is a consequence of endoplasmic reticulum retention due to channel misfolding; and 2) to test the hypothesis that in the majority of high-grade gliomas ASIC2 gene expression is transcriptionally regulated by factors specific to the brain tumor microenvironment. We anticipate that this work will provide new fundamental insights into the molecular mechanisms involved in the regulation of amiloride-sensitive Na + channels in brain tumors. Moreover, this work will provide important clues as to the role of these channels in the pathogenesis and life cycle of glioma cells.
| Kapoor, Niren; Lee, William; Clark, Edlira et al. (2011) Interaction of ASIC1 and ENaC subunits in human glioma cells and rat astrocytes. Am J Physiol Cell Physiol 300:C1246-59 |
| Kapoor, Niren; Bartoszewski, Rafal; Qadri, Yawar J et al. (2009) Knockdown of ASIC1 and epithelial sodium channel subunits inhibits glioblastoma whole cell current and cell migration. J Biol Chem 284:24526-41 |
| Griguer, Corinne E; Oliva, Claudia R; Gobin, Eric et al. (2008) CD133 is a marker of bioenergetic stress in human glioma. PLoS One 3:e3655 |
| Vila-Carriles, Wanda H; Zhou, Zhen-Hong; Bubien, James K et al. (2007) Participation of the chaperone Hsc70 in the trafficking and functional expression of ASIC2 in glioma cells. J Biol Chem 282:34381-91 |
| Benos, Dale J; Bashari, Edlira; Chaves, Jose M et al. (2007) The ups and downs of peer review. Adv Physiol Educ 31:145-52 |
| Ross, Sandra B; Fuller, Catherine M; Bubien, James K et al. (2007) Amiloride-sensitive Na+ channels contribute to regulatory volume increases in human glioma cells. Am J Physiol Cell Physiol 293:C1181-5 |
| Bubien, James K; Benos, Dale J (2006) Molecular pH Probes: mediators of angina and ischemic preconditioning? Circ Res 99:453-4 |
| Vila-Carriles, Wanda H; Kovacs, Gergely Gy; Jovov, Biljana et al. (2006) Surface expression of ASIC2 inhibits the amiloride-sensitive current and migration of glioma cells. J Biol Chem 281:19220-32 |
| Kovacs, Gergely Gy; Zsembery, Akos; Anderson, Susan J et al. (2005) Changes in intracellular Ca2+ and pH in response to thapsigargin in human glioblastoma cells and normal astrocytes. Am J Physiol Cell Physiol 289:C361-71 |
