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

Abstract

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.

Combinatorial delivery of CPI444 and vatalanib loaded on PEGylated graphene oxide as an effective nanoformulation to target glioblastoma multiforme: In vitro evaluation

“…These observations suggest that combinatorial treatment of CPI444 with vatalanib with the aid of GO-PEG is effective in reducing the cellular calcium pool of GBM U87 cells. This is a very promising observation as Ca 2+ levels play a critical role not only in GSC proliferation and in glial cell function that helps in the survival and fate determination process ( 44 , 47 ).…”

“…Glioblastoma multiforme (GBM) is a type of high-grade primary brain cancer that comprises a subpopulation called glioblastoma stem cells (GSC), which are responsible for tumor initiation, development, and recurrence following treatment ( 3 ). Calcium (Ca 2+ ) is a secondary messenger that plays a vital role in cell proliferation, cell death, differentiation, migration, metabolism, neural plasticity, and gene transcription, among other processes ( 43 , 44 ). Calcium signaling is reported to have a significant impact on neuronal cell development and function ( 45 ).…”

A Calcium-Related Immune Signature in Prognosis Prediction of Patients With Glioma

“…Recent research showed that major modifications appear in the regulation of the SOC mechanism in glioblastoma and glioblastoma stem cells, compared to normal brain tissues ( Robil et al, 2015 ). Moreover, SOC inhibitors diminished proliferation and substantially reduces the self-renewal capacities of glioblastoma stem cells ( Terrié et al, 2021 ). However, our 18 calcium-related genes did not involve in the SOCs or ROCs.…”

New Insights into TRP Ion Channels in Stem Cells

“…Early evidence showed that TRPC1 presented in glioblastoma stem cells (GSC) with store-operated channel proteins of Orai1 and STIM1 [ 56 ].…”

“…Studies have identified that TRPCs can interact with STIM1 and Orai1 components to constitute store-operated Ca 2+ entry. Regarding the complex of TRPC1 with STIM1 and Orai1 in NSCs, NPCs and GSCs may contribute to store-dependent Ca 2+ signaling [ 20 , 56 , 66 ].…”