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Article

Store-Operated Calcium Channels Control Proliferation and Self-Renewal of Cancer Stem Cells from Glioblastoma

1
CNRS ERL 7003, Signalisation et Transports Ioniques Membranaires, University of Poitiers, CEDEX 09, 86073 Poitiers, France
2
EA 4379, Signalisation et Transports Ioniques Membranaires, University of Poitiers, CEDEX 09, 86073 Poitiers, France
3
CRCINA-UMR 1232 INSERM, Université de Nantes, CEDEX 01, 44007 Nantes, France
4
CNRS GDR3697, Micronit “Microenvironment of Tumor Niches”, 37000 Tours, France
*
Author to whom correspondence should be addressed.
Co-last authors.
Academic Editors: Juan A. Rosado and Tarik Smani
Cancers 2021, 13(14), 3428; https://doi.org/10.3390/cancers13143428
Received: 1 June 2021 / Revised: 5 July 2021 / Accepted: 5 July 2021 / Published: 8 July 2021
(This article belongs to the Special Issue Calcium Signaling Remodeling and Functional Role in Cancer Cells)
Glioblastoma is a high-grade primary brain tumor that contains a subpopulation of cells called glioblastoma stem cells, which are responsible for tumor initiation, growth and recurrence after treatment. Recent transcriptomic studies have highlighted that calcium pathways predominate in glioblastoma stem cells. Calcium channels have the ability to transduce signals from the microenvironment and are therefore ideally placed to control cellular behavior. Using multiple approaches, we demonstrate in five different primary cultures, previously derived from surgical specimens, that glioblastoma stem cells express store-operated channels (SOC) that support calcium entry into these cells. Pharmacological inhibition of SOC dramatically reduces cell proliferation and stem cell self-renewal in these cultures. By identifying SOC as a critical mechanism involved in the maintenance of the stem cell population in glioblastoma, our study will contribute to the framework for the identification of new therapies against this deadly tumor.
Glioblastoma is the most frequent and deadly form of primary brain tumors. Despite multimodal treatment, more than 90% of patients experience tumor recurrence. Glioblastoma contains a small population of cells, called glioblastoma stem cells (GSC) that are highly resistant to treatment and endowed with the ability to regenerate the tumor, which accounts for tumor recurrence. Transcriptomic studies disclosed an enrichment of calcium (Ca2+) signaling transcripts in GSC. In non-excitable cells, store-operated channels (SOC) represent a major route of Ca2+ influx. As SOC regulate the self-renewal of adult neural stem cells that are possible cells of origin of GSC, we analyzed the roles of SOC in cultures of GSC previously derived from five different glioblastoma surgical specimens. Immunoblotting and immunocytochemistry experiments showed that GSC express Orai1 and TRPC1, two core SOC proteins, along with their activator STIM1. Ca2+ imaging demonstrated that SOC support Ca2+ entries in GSC. Pharmacological inhibition of SOC-dependent Ca2+ entries decreased proliferation, impaired self-renewal, and reduced expression of the stem cell marker SOX2 in GSC. Our data showing the ability of SOC inhibitors to impede GSC self-renewal paves the way for a strategy to target the cells considered responsible for conveying resistance to treatment and tumor relapse. View Full-Text
Keywords: glioblastoma; glioma; cancer stem cell; calcium channel; store-operated channel; TRPC; Orai; STIM glioblastoma; glioma; cancer stem cell; calcium channel; store-operated channel; TRPC; Orai; STIM
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MDPI and ACS Style

Terrié, E.; Déliot, N.; Benzidane, Y.; Harnois, T.; Cousin, L.; Bois, P.; Oliver, L.; Arnault, P.; Vallette, F.; Constantin, B.; Coronas, V. Store-Operated Calcium Channels Control Proliferation and Self-Renewal of Cancer Stem Cells from Glioblastoma. Cancers 2021, 13, 3428. https://doi.org/10.3390/cancers13143428

AMA Style

Terrié E, Déliot N, Benzidane Y, Harnois T, Cousin L, Bois P, Oliver L, Arnault P, Vallette F, Constantin B, Coronas V. Store-Operated Calcium Channels Control Proliferation and Self-Renewal of Cancer Stem Cells from Glioblastoma. Cancers. 2021; 13(14):3428. https://doi.org/10.3390/cancers13143428

Chicago/Turabian Style

Terrié, Elodie, Nadine Déliot, Yassine Benzidane, Thomas Harnois, Laëtitia Cousin, Patrick Bois, Lisa Oliver, Patricia Arnault, François Vallette, Bruno Constantin, and Valérie Coronas. 2021. "Store-Operated Calcium Channels Control Proliferation and Self-Renewal of Cancer Stem Cells from Glioblastoma" Cancers 13, no. 14: 3428. https://doi.org/10.3390/cancers13143428

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