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

Abstract

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.

Dexamethasone in Patients with Glioblastoma: A Systematic Review and Meta-Analysis

“…Dexamethasone also reduces temozolomide-mediated apoptosis in human glioblastoma cells [48][49][50], possibly through O6-methylguanine-DNA methyltransferase (MGMT) upregulation, which results in an increased temozolomide resistance [51,52]. Interestingly, some preclinical studies have found that dexamethasone can also reduce glioblastoma invasiveness through various mechanisms [53][54][55][56][57].…”

Doxycycline Induces Apoptosis of Brucella Suis S2 Strain-Infected HMC3 Microglial Cells by Activating Calreticulin-Dependent JNK/p53 Signaling Pathway

“…As a multifunctional protein in the endoplasmic reticulum, CALR plays a role in anti-apoptosis through regulating calcium ion concentration ( Gold et al., 2010 ). Investigators have previously shown that endothelial cells pretreated with exogenous CALR protein can inhibit expression of apoptosis-associated proteins and reduce apoptosis ( Nair et al., 2018 ). Our results similarly showed that HMC3 cells infected with B. suis S2 at an MOI of 50 for 2 h can promote expression of CALR protein and inhibit apoptosis.…”