Connexin 43 and Sonic Hedgehog Pathway Interplay in Glioblastoma Cell Proliferation and Migration

Glioblastoma (GBM) represents the most common primary brain tumor within the adult population. Current therapeutic options are still limited by high rate of recurrences and signalling axes that promote GBM aggressiveness. The contribution of gap junctions (GJs) to tumor growth and progression has be...

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Bibliographic Details
Published in:Biology (Basel, Switzerland) Switzerland), 2021-08, Vol.10 (8), p.767
Main Authors: Torrisi, Filippo, Alberghina, Cristiana, Lo Furno, Debora, Zappalà, Agata, Valable, Samuel, Li Volti, Giovanni, Tibullo, Daniele, Vicario, Nunzio, Parenti, Rosalba
Format: Article
Language:English
Subjects:
Agonists
Autocrine signalling
Brain cancer
Brain tumors
Cancer
Cell activation
Cell differentiation
Cell fate
Cell growth
Cell interactions
Cell migration
Cell proliferation
Communication
connexin
Connexin 43
Cytotoxicity
Epigenetics
gap junction
Gap junctions
GBM
GLI1
Glioblastoma
Hedgehog protein
Intracellular signalling
Life Sciences
Medical prognosis
Metabolism
Metabolites
Molecular modelling
Neurobiology
Neurons and Cognition
Paracrine signalling
Penicillin
Signal transduction
smoothened
Stem cells
Tumor cells
Tumor microenvironment
Tumorigenesis
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Summary:Glioblastoma (GBM) represents the most common primary brain tumor within the adult population. Current therapeutic options are still limited by high rate of recurrences and signalling axes that promote GBM aggressiveness. The contribution of gap junctions (GJs) to tumor growth and progression has been proven by experimental evidence. Concomitantly, tumor microenvironment has received increasing interest as a critical process in dysregulation and homeostatic escape, finding a close link between molecular mechanisms involved in connexin 43 (CX43)-based intercellular communication and tumorigenesis. Moreover, evidence has come to suggest a crucial role of sonic hedgehog (SHH) signalling pathway in GBM proliferation, cell fate and differentiation. Herein, we used two human GBM cell lines, modulating SHH signalling and CX43-based intercellular communication in in vitro models using proliferation and migration assays. Our evidence suggests that modulation of the SHH effector smoothened (SMO), by using a known agonist (i.e., purmorphamine) and a known antagonist (i.e., cyclopamine), affects the CX43 expression levels and therefore the related functions. Moreover, SMO activation also increased cell proliferation and migration. Importantly, inhibition of CX43 channels was able to prevent SMO-induced effects. SHH pathway and CX43 interplay acts inducing tumorigenic program and supporting cell migration, likely representing druggable targets to develop new therapeutic strategies for GBM.
ISSN:2079-7737
2079-7737
DOI:10.3390/biology10080767