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The Journal of Neuroscience, July 15, 1999, 19(14):5942-5954
Modulation of Glioma Cell Migration and Invasion Using
Cl and K+ Ion Channel Blockers
Liliana
Soroceanu,
Timothy
J.
Manning Jr, and
Harald
Sontheimer
Department of Neurobiology, The University of Alabama at
Birmingham, Birmingham, Alabama 35294-0021
Human malignant gliomas are highly invasive tumors. Mechanisms that
allow glioma cells to disseminate, migrating through the narrow
extracellular brain spaces are poorly understood. We recently demonstrated expression of large voltage-dependent chloride
(Cl ) currents, selectively expressed by human
glioma cells in vitro and in situ
(Ullrich et al., 1998). Currents are sensitive to several
Cl channel blockers, including chlorotoxin (Ctx),
(Ullrich and Sontheimer, 1996; Ullrich et al., 1996),
tetraethylammonium chloride (TEA), and tamoxifen (Ransom and
Sontheimer, 1998). Using Transwell migration assays, we show that
blockade of glioma Cl channels specifically
inhibits tumor cell migration in a dose-dependent manner. Ctx (5 µM), tamoxifen (10 µM), and TEA (1 mM) also prevented invasion of human glioma cells into
fetal rat brain aggregates, used as an in vitro model to
assess tumor invasiveness. Anion replacement studies suggest that
permeation of chloride ions through glioma chloride channel is
obligatory for cell migration. Osmotically induced cell swelling and
subsequent regulatory volume decrease (RVD) in cultured glioma cells
were reversibly prevented by 1 mM TEA, 10 µM
tamoxifen, and irreversibly blocked by 5 µM Ctx added to
the hypotonic media. Cl fluxes associated with
adaptive shape changes elicited by cell swelling and RVD in glioma
cells were inhibited by 5 µM Ctx, 10 µM
tamoxifen, and 1 mM TEA, as determined using the
Cl-sensitive fluorescent dye
6-methoxy-N-ethylquinolinium iodide. Collectively, these
data suggest that chloride channels in glioma cells may enable tumor
invasiveness, presumably by facilitating cell shape and cell volume
changes that are more conducive to migration and invasion.
Key words:
chlorotoxin; glioma invasiveness; chloride channel; RVD; MEQ; cell migration
Copyright © 1999 Society for Neuroscience 0270-6474/99/19145942-13$05.00/0
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