Dexamethasone-Mediated Upregulation of Calreticulin Inhibits Primary Human Glioblastoma Dispersal Ex Vivo

• Published in: International journal of molecular sciences Vol. 19; no. 2; p. 572
• Main Authors: Nair, Mohan, Romero, Juan, Mahtabfar, Aria, Meleis, Ahmed M, Foty, Ramsey A, Corbett, Siobhan A
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 14.02.2018; MDPI
• Subjects: Brain cancer; Brain slice preparation; brain slices; Brain tumors; Calreticulin; Compaction; Dexamethasone; Dispersal; Dispersion; Edema; Explants; Fibronectin; Glioblastoma; inhibition; Integrins; Neurospheres; Proteins; Retina; retina model; siRNA; Steroids; Tumors; Velocity; dexamethasone; glioblastoma; calreticulin; dispersal; inhibition; brain slices; retina model
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms19020572

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 α5 integrin activity, leading to restoration of fibronectin matrix assembly (FNMA), increased neurosphere cohesion, and reduction of neurosphere dispersal velocity (DV). How Dex specifically activates α5 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 α5 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.