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Advanced Neurology TG100-115 suppresses glioblastoma cell functions

1. Introduction 3 and Notch signaling, and is activated by prostaglandin
E2 via the prostaglandin E receptor 3/protein kinase A
Glioblastomas (GBMs) are characterized by aggressive pathway to promote GBM cell proliferation and motility.
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growth and invasiveness, significantly affecting patient These findings collectively underscore TRPM7 as a critical
survival, neurological function, psychological well-being, regulator of GBM malignancy and a potential therapeutic
and overall quality of life. Despite advancements in target. However, the relative contribution of the kinase
1
therapeutic strategies combining surgery, temozolomide domain to GBM regulation, as compared to that of the ion
chemotherapy, and radiotherapy, GBMs are associated channel, remains insufficiently defined.
with a poor prognosis, with a median survival of
14.6 months after diagnosis. The ongoing challenges The kinase domain of TRPM7 retains functional
2
pertaining to drug resistance, the blood–brain barrier, distinctiveness, with unique implications in human cancer
and tumor heterogeneity highlight the need for new pathogenesis, and mediates tumorigenic processes through
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therapeutic approaches. Genomic analyses of gliomas have the phosphorylation of specific substrates. In contrast to
revealed a wide range of deregulated genes with somatic the ion channel domain, which primarily mediates cell
mutations, including TERT, TP53, IDH1, ATRX, and TTN, proliferation, the kinase domain is specifically required for
among others, providing important insights into glioma cytoskeletal regulation and metastatic behavior. Notably,
pathogenesis. Building on these findings, recent studies deletion or inactivation of this domain significantly
3-5
have advanced the development of therapies targeting reduces migratory and invasive capacities without
critical signaling pathways, including the epidermal growth affecting proliferation. 20,21 Therefore, selectively inhibiting
factor receptor, phosphoinositide 3-kinase (PI3K)/protein the TRPM7 kinase domain may offer a therapeutic strategy
kinase B (Akt)/mammalian target of rapamycin (mTOR) to suppress cancer metastasis while minimizing effects on
axis, and vascular endothelial growth factor, along with the normal cell growth.
exploration of immune checkpoint inhibitors. However, TG100-115, identified for its potent inhibition of
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the lack of effective treatment options underscores the TRPM7 kinase in 2017, demonstrates a potency surpassing
urgent need for deeper exploration of the molecular the previously known TRPM7 kinase inhibitor, rottlerin,
mechanisms of GBM to discover novel therapeutic targets. by over 70-fold. In addition, TG100-115 significantly
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Transient receptor potential melastatin 7 (TRPM7) inhibits the migratory and invasive abilities of breast
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is a non-selective divalent cation channel that facilitates cancer cells. TG100-115 was initially characterized as
the influx of ions such as calcium, magnesium, and zinc. a potent inhibitor of PI3K, exhibiting selective affinity
TRPM7 contains an unusual α-kinase domain within its for the PI3K-γ and PI3K-δ isoforms. In rigorous animal
C-terminal region, enabling its dual function as both an models of myocardial infarction, TG100-115 demonstrated
ion channel and a kinase. TRPM7 is widely expressed in significant cardioprotective effects, reducing infarct size
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various tissues and has been implicated in the progression and preserving myocardial function. At present, TG100-
of multiple malignancies, including pancreatic, breast, 115 is the only potent inhibitor known to selectively target
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gastric, and nasopharyngeal cancers, as well as GBM. the TRPM7 kinase domain, offering valuable insights into
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Accumulating evidence indicates that TRPM7 plays the kinase-specific pathophysiological role of TRPM7 in
a pivotal role in the progression of GBM. Inhibition GBM. Such inhibitors serve as important pharmacological
of TRPM7 using compounds, such as carvacrol and tools for investigating the biological functions mediated by
waixenicin A, has been shown to suppress GBM cell TRPM7 kinase activity.
proliferation, migration, and invasion both in vitro In this study, we investigated the impact of TG100-115
and in vivo while inducing apoptosis in GBM cells. 12,13 on the proliferation, migration, and invasion of the GBM
Conversely, pharmacological activation of TRPM7 using cell line U251. Furthermore, we explored its effects on
naltriben enhances the migratory and invasive capabilities apoptosis and potential molecular mechanisms, aiming to
of GBM cells, highlighting its pro-tumorigenic function. provide insights into novel therapeutic strategies for GBM
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Mechanistically, TRPM7 regulates key oncogenic treatment.
pathways, including the PI3K/Akt and mitogen-activated
protein kinase (MAPK) kinase (MEK)/extracellular signal- 2. Materials and methods
regulated kinase (ERK) 12,13,15,16 pathways, and modulates
the expression of matrix metalloproteinase 2, contributing 2.1. Cell culture
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to tumor cell invasion. Furthermore, TRPM7 has been Human GBM cell line U251 was obtained from the
implicated in the maintenance of glioma stem-like cells American Type Culture Collection (United States of
through signal transducer and activator of transcription America [USA]). Cell culture procedures followed

Volume 4 Issue 3 (2025) 89 doi: 10.36922/AN025110023