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Dexamethasone-Mediated Upregulation of Calreticulin Inhibits Primary Human
Glioblastoma Dispersal Ex Vivo
#MMPMID29443896
Nair M
; Romero J
; Mahtabfar A
; Meleis AM
; Foty RA
; Corbett SA
Int J Mol Sci
2018[Feb]; 19
(2
): ? PMID29443896
show ga
Dispersal of Glioblastoma (GBM) renders localized therapy ineffective and is a
major cause of recurrence. Previous studies have demonstrated that Dexamethasone
(Dex), a drug currently used to treat brain tumor-related edema, can also
significantly reduce dispersal of human primary GBM cells from neurospheres. It
does so by triggering ?5 integrin activity, leading to restoration of fibronectin
matrix assembly (FNMA), increased neurosphere cohesion, and reduction of
neurosphere dispersal velocity (DV). How Dex specifically activates ?5 integrin
in these GBM lines is unknown. Several chaperone proteins are known to activate
integrins, including calreticulin (CALR). We explore the role of CALR as a
potential mediator of Dex-dependent induction of ?5 integrin activity in primary
human GBM cells. We use CALR knock-down and knock-in strategies to explore the
effects on FNMA, aggregate compaction, and dispersal velocity in vitro, as well
as dispersal ex vivo on extirpated mouse retina and brain slices. We show that
Dex increases CALR expression and that siRNA knockdown suppresses Dex-mediated
FNMA. Overexpression of CALR in GBM cells activates FNMA, increases compaction,
and decreases DV in vitro and on explants of mouse retina and brain slices. Our
results define a novel interaction between Dex, CALR, and FNMA as inhibitors of
GBM dispersal.
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