In vitro suppression of glioblastoma cell functions by TG100-115, a transient receptor potential melastatin 7 kinase inhibitor

Abstract

Glioblastomas (GBMs) are highly aggressive and lethal primary brain tumors, known for their rapid proliferation, diffuse infiltration, and resistance to conventional therapies. Recent studies have highlighted the involvement of transient receptor potential melastatin 7 (TRPM7) in regulating GBM progression through its dual function as an ion channel and a serine/threonine protein kinase. TG100-115, initially characterized as a phosphoinositide 3-kinase γ/δ inhibitor, has recently been identified as a novel inhibitor of TRPM7 kinase. However, its potential pharmacological effects in GBM cells have not been fully elucidated. In this study, we investigated the anti-GBM effects of TG100-115 in U251 glioma cells. Cell viability and proliferation were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, whereas cell motility and invasiveness were determined through wound healing and transwell assays, respectively. Western blotting was used to detect the expression of key proteins involved in the apoptotic and molecular signaling pathways. Our findings revealed that TG100-115 significantly diminished the viability of U251 cells by promoting apoptosis while concurrently inhibiting the migratory and invasive activities of GBM cells. Mechanistically, TG100-115 enhanced apoptotic signaling by modulating B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein, and cleaved caspase-3 levels. It also altered the phosphorylation status of protein kinase B and cofilin - both critical for cell survival and cytoskeletal dynamics. In conclusion, these findings suggest that TG100-115, by targeting TRPM7 kinase, exhibits promising therapeutic potential for GBM treatment and provides novel insights into targeting TRPM7-associated pathways in aggressive brain tumors.

Graphical abstract

Keywords

Transient receptor potential melastatin 7 kinase / TG100-115 / Glioblastoma / Proliferation / Migration / Invasion

Funding

This work was supported by the following grants: Canadian Institutes of Health Research (CIHR PJT-153155) to ZPF and the Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grants (RGPIN- 2016-04574 and RGPIN-2022-04589) to HSS.

Conflict of interest

Hong- Shuo Sun is an Editorial Board Member, and Zhong- Ping Feng serves as an Associate Editor for this journal, but they were not in any way involved in the editorial and peer-review process conducted for this paper, directly or indirectly. Separately, other authors declared that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.

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