title: Surface expression of ASIC2 inhibits the amiloride-sensitive current and migration of glioma cells.
abstract: Gliomas are primary brain tumors with a complex biology characterized by antigenic and genomic heterogeneity and a propensity for invasion into normal brain tissue. High grade glioma cells possess a voltage-independent, amiloride-inhibitable, inward Na+ current. This current does not exist in normal astrocytes or low grade tumor cells. Inhibition of this conductance decreases glioma growth and cell migration making it a potential therapeutic target. Our previous results have shown that the acid-sensing ion channels (ASICs), members of the epithelial Na+ channel (ENaC)/degenerin (DEG) family of ion channels are part of this current pathway. We hypothesized that one member of the ENaC/DEG family, ASIC2, is retained intracellularly and that it is the lack of functional expression of ASIC2 at the cell surface that results in hyperactivity of this conductance in high grade gliomas. In this study we show that the chemical chaperone, glycerol, and the transcriptional regulator, sodium 4-phenylbutyrate, inhibit the constitutively activated inward current and reduce cell growth and migration in glioblastoma multiforme. The results suggest that these compounds induce the movement of ASIC2 to the plasma membrane, and once there, the basally active inward current characteristic of glioma cells is abolished by inherent negative regulatory mechanisms. This in turn compromises the ability of the glioma cell to migrate and proliferate. These results support the hypothesis that the conductance pathway in high grade glioma cells is comprised of ENaC/DEG subunits and that abolishing this channel activity promotes a reversion of a high grade glioma cell to a phenotype resembling that of normal astrocytes.
authors.affiliation: Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: Wanda H
authors.initials: WH
authors.lastname: Vila-Carriles
authors.forename: Gergely Gy
authors.initials: GG
authors.lastname: Kovacs
authors.forename: Biljana
authors.initials: B
authors.lastname: Jovov
authors.forename: Zhen-Hong
authors.initials: ZH
authors.lastname: Zhou
authors.forename: Amit K
authors.initials: AK
authors.lastname: Pahwa
authors.forename: Garrett
authors.initials: G
authors.lastname: Colby
authors.forename: Ogenna
authors.initials: O
authors.lastname: Esimai
authors.forename: G Yancey
authors.initials: GY
authors.lastname: Gillespie
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Mapstone
authors.forename: James M
authors.initials: JM
authors.lastname: Markert
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Fuller
authors.forename: James K
authors.initials: JK
authors.lastname: Bubien
authors.forename: Dale J
authors.initials: DJ
authors.lastname: Benos
mesh_terms: D062565:Acid Sensing Ion Channels; D000584:Amiloride / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000473:pathology*; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D005909:Glioblastoma / Q000473:pathology; D005910:Glioma / Q000473:pathology*; D005990:Glycerol / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology*; D010654:Phenylbutyrates / Q000494:pharmacology; D012964:Sodium / Q000737:chemistry; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000378:metabolism / Q000502:physiology*
chemical_list: D062565:Acid Sensing Ion Channels; D000970:Antineoplastic Agents; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010654:Phenylbutyrates; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D000584:Amiloride; C075773:4-phenylbutyric acid; D012964:Sodium; D005990:Glycerol