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Advanced Neurology TG100-115 suppresses glioblastoma cell functions

inhibition of TRPM7 kinase, rather than PI3K blockade. recognized inhibitors (exhibiting an IC of 1.07 ±
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Further studies using small interfering RNA targeting 0.14 µM), as demonstrated by utilizing the cyclic adenosine
TRPM7 or kinase-mutated cell lines are needed to clarify monophosphate response element-binding protein peptide
the inhibitory activity of TG100-115 on TRPM7 kinase. as an in vitro substrate and adopting an assay system for
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The MAPK/ERK pathway contributes to cancer kinase inhibitory compounds. Despite the demonstrated
progression and treatment resistance. ERK1/2 is activated capability of TG100-115 to reversibly inhibit TRPM7-
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by MEK phosphorylation and phosphorylates transcription like currents, this effect required significantly higher
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factors, influences gene expression, and promotes cancer, concentrations, specifically 100 µM. Interestingly, our
alongside GBM cell proliferation and invasion. We study concluded that TG100-115 does not alter the protein
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previously reported that TRPM7 downregulation reduced expression of TRPM7, indicating that its inhibitory action
the phosphorylation of ERK1/2. However, we observed is primarily linked to the kinase domain, rather than
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that TG100-115 showed no significant effect on ERK1/2, affecting the overall expression of the TRPM7 channel-
suggesting that TRPM7 regulates MAPK/ERK signaling kinase. Such findings highlight the inhibitory potency
potentially through its channel domain, but not its kinase of TG100-115 in targeting the kinase-specific functions
domain. This is worthy of further investigation. of TRPM7, making it a valuable tool for studying the
functional implications of TRPM7 kinase in GBMs.
Bcl-2, an anti-apoptotic molecule, is overexpressed in
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GBM and other types of cancer, enhancing resistance 5. Conclusion
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to cytotoxic treatments. Conversely, Bax, a pro-apoptotic
Bcl-2 family member, when released from Bcl-2 inhibition In summary, this study provides compelling in vitro
through pharmacological means, promotes apoptosis in evidence for the potential therapeutic efficacy of TG100-
GBM cells both in vitro and in vivo. Caspase-3 activation 115 in GBMs. The potential molecular mechanism
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by cleavage promotes apoptosis. Caspase-3 activity is underlying the inhibitory effects of TG100-115 on cell
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modulated by the Bcl-2/Bax balance, where Bax leads to the viability, proliferation, migration, and invasion involves
release of cytochrome c and a subsequent cascade of caspase blocking TRPM7 kinase, thus altering multiple signaling
activations. 13,17 We found that TG100-115 diminished pathways, including Bcl-2/Bax/caspase-3, Akt, and cofilin.
Bcl-2 expression and augmented Bax expression, while These findings collectively position TG100-115 as a
also increasing cleaved caspase-3 expression. Our promising candidate for further exploration in preclinical
results demonstrate that TG100-115 promotes GBM cell and clinical studies.
apoptosis through the Bcl-2/Bax/caspase-3 pathway, likely
contributing to its inhibitory effects on GBM cell viability. Acknowledgments
Cofilin is crucial for cell motility, particularly in tumor We would like to thank the Second Affiliated Hospital of
cell migration and invasion. 29,41 Its phosphorylated state Guangdong Medical University and the Zhuhai Campus of
suppresses activity, affecting actin filament dynamics and Zunyi Medical University for their valuable support and
cellular movement, thus underscoring its importance in contributions to this study.
cancer metastasis. 29,42 Park et al. have highlighted cofilin Funding
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upregulation in human GBM tissues and its potential as a
therapeutic target, with its inhibition reducing glioma cell This work was supported by the following grants: Canadian
motility. Our laboratory has shown that TRPM7 inhibitors Institutes of Health Research (CIHR PJT-153155) to
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decreased cofilin activity, hindering GBM cell invasion and ZPF and the Natural Sciences and Engineering Research
migration. 12,13 Consistently, this study also showed that Council of Canada (NSERC) Discovery Grants (RGPIN-
TG100-115 increased cofilin phosphorylation. Intriguingly, 2016-04574 and RGPIN-2022-04589) to HSS.
recent research indicates that the TRPM7 kinase domain
interacts with cofilin in neuroblastoma cells and mouse Conflict of interest
brains. 44,45 Cofilin phosphorylation can also be regulated Hong-Shuo Sun is an Editorial Board Member, and Zhong-
by the Akt/mTOR pathway, influencing melanoma cell Ping Feng serves as an Associate Editor for this journal,
behaviors, which suggests cofilin as a potential downstream but they were not in any way involved in the editorial and
effector of Akt signaling. Therefore, TRPM7 kinase may peer-review process conducted for this paper, directly or
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modulate cofilin activity through Akt-dependent signaling, indirectly. Separately, other authors declared that they
affecting GBM migration and invasion. have no known competing financial interests or personal
TG100-115 was previously identified as a significantly relationships that could have influenced the work reported
more potent inhibitor of the TRPM7 kinase than other in this paper.

Volume 4 Issue 3 (2025) 96 doi: 10.36922/AN025110023