Abstract
We previously demonstrated that Annexin A2 (ANXA2) is a pivotal mediator of the pro-oncogenic
features displayed by glioblastoma (GBM) tumors, the deadliest adult brain malignancies,
being involved in cell stemness, proliferation and invasion, thus negatively impacting
patient prognosis. Based on these results, we hypothesized that compounds able to
revert ANXA2-dependent transcriptional features could be exploited as reliable treatments
to inhibit GBM cell aggressiveness by hampering their proliferative and migratory
potential. Transcriptional signatures obtained by the modulation of ANXA2 activity/levels
were functionally mapped through the QUADrATiC bioinformatic tool for compound identification.
Selected compounds were screened by cell proliferation and migration assays in primary
GBM cells, and we identified Homoharringtonine (HHT) as a potent inhibitor of GBM
cell motility and proliferation, without affecting their viability. A further molecular
characterization of the effects displayed by HHT, confirmed its ability to inhibit
a transcriptional program involved in cell migration and invasion. Moreover, we demonstrated
that the multiple antitumoral effects displayed by HHT are correlated to the inhibition
of a platelet derived growth factor receptor α (PDGFRα)-dependent intracellular signaling
through the impairment of Signal transducer and activator of transcription 3 (STAT3)
and Ras homolog family member A (RhoA) axes. Our results demonstrate that HHT may
act as a potent inhibitor of cancer cell proliferation and invasion in GBM, by hampering
multiple PDGFRα-dependent oncogenic signals transduced through the STAT3 and RhoA
intracellular components, finally suggesting its potential transferability for achieving
an effective impairment of peculiar GBM hallmarks.
Abbreviations:
5-ALA (5-aminolevulinic acid), ANXA2 (Annexin A2), AZA (5′-Azacytidine), bFGF (basic Fibroblast Growth Factor), BOR (Bortezomib), CML (Chronic Myeloid Leukemia), DEGs (Differentially Expressed Genes), DIG (Digitoxin), ECM (Extracellular Matrix), EGF (Epidermal Growth Factor), EMT (Epithelial to Mesenchymal Transition), FA (Focal Adhesion), FBS (Foetal Bovine Serum), FDA (Food and Drug Administration), GBM (Glioblastoma), GEP (Gene Expression Profile), GI50 (Growth Inhibition 50), gw (gestational weeks), HHT (Homoharringtonine), hpi (hours post-injection), MFI (Mean Fluorescence Intensity), NIC (Niclosamide), OUA (Ouabain), PDGFRα (Platelet Derived Growth Factor Receptor α), PRO (Probenecid), PVDF (polyvinylidene difluoride), S.E.M. (Standard Error of the Mean), TMZ (Temozolomide), WB (Western Blot)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: July 01, 2022
Accepted:
June 27,
2022
Received in revised form:
June 24,
2022
Received:
February 3,
2022
Footnotes
Elena Porcù and Francesca Maule contributed equally to this work.
Identification
Copyright
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