Inhibition of TRPM7 with waixenicin A reduces glioblastoma cellular functions

Wong, Raymond; Gong, Haifan; Alanazi, Rahmah; Bondoc, Andrew; Luck, Amanda; Sabha, Nesrin; Horgen, F. David; Fleig, Andrea; Rutka, James T.; Feng, Zhong‐Ping; Sun, Hong‐Shuo

doi:10.1016/j.ceca.2020.102307

Cited by 14 publications

(15 citation statements)

References 46 publications

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“…TRP-melastatin7 (TRPM7) promotes migration and invasion of glioma via activation of STAT3 and Notch signaling pathways ( Liu et al, 2014 ), while glioma invasion was reduced in cells transfected with a TRPM7 mutant ( Wan et al, 2019 ). Pharmacological inhibition or siRNA for TRPM7 also reduces migration and invasion in human glioma cells ( Leng et al, 2015 ) and antagonist for TRPM7 reduces various cellular functions such as proliferation, viability, migration, and invasion in both U251/U87 cells ( Wong et al, 2020 ). Furthermore, a TRPM8 agonist increases cytosolic Ca 2+ , subsequently leading to activation of Ca 2+ -activated K + channels that induce glioma cell migration ( Wondergem and Bartley, 2009 ).…”

Section: Calcium Signaling In Glioblastoma Is Related To Migration and Invasionmentioning

confidence: 99%

Mechanisms of Invasion in Glioblastoma: Extracellular Matrix, Ca2+ Signaling, and Glutamate

Kim

Han

2021

Front. Cell. Neurosci.

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Glioblastoma (GBM) is the most common and malignant form of primary brain tumor with a median survival time of 14–16 months in GBM patients. Surgical treatment with chemotherapy and radiotherapy may help increase survival by removing GBM from the brain. However, complete surgical resection to eliminate GBM is almost impossible due to its high invasiveness. When GBM cells migrate to the brain, they interact with various cells, including astrocytes, neurons, endothelial cells, and the extracellular matrix (ECM). They can also make their cell body shrink to infiltrate into narrow spaces in the brain; thereby, they can invade regions of the brain and escape from surgery. Brain tumor cells create an appropriate microenvironment for migration and invasion by modifying and degrading the ECM. During those processes, the Ca2+ signaling pathway and other signaling cascades mediated by various ion channels contribute mainly to gene expression, motility, and invasion of GBM cells. Furthermore, GBM cells release glutamate, affecting migration via activation of ionotropic glutamate receptors in an autocrine manner. This review focuses on the cellular mechanisms of glioblastoma invasion and motility related to ECM, Ca2+ signaling, and glutamate. Finally, we discuss possible therapeutic interventions to inhibit invasion by GBM cells.

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Section: Calcium Signaling In Glioblastoma Is Related To Migration and Invasionmentioning

confidence: 99%

Mechanisms of Invasion in Glioblastoma: Extracellular Matrix, Ca2+ Signaling, and Glutamate

Kim

Han

2021

Front. Cell. Neurosci.

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“…PI3K/Akt is one of the signalling pathways that is involved in the regulation of proliferation, migration and invasion of GBM cells. Previous in vitro studies from our lab showed that inhibition of TRPM7 reduced the activity of various signalling proteins that contribute to GBM cellular functions including Akt (Chen, Barszczyk, et al, 2015; Chen, Turlova, et al, 2015; Wong et al, 2020). We have shown that the expression level of p‐Akt was significantly reduced in (500 μM) carvacrol‐treated cells (Chen, Barszczyk, et al, 2015).…”

Section: Resultsmentioning

confidence: 90%

“…This effect of TRPM7 potentiation is likely mediated through the upregulation of MMP‐2 as well as MAPK/ERK signalling (Wong et al, 2017). In addition, we have shown in vitro and in vivo the effect of TRPM7 specific inhibitor waixenicin A on GBM cellular functions (Wong et al, 2020). Inhibition of TRPM7 using waixenicin A in GBM cell lines U87 and U251 reduced TRPM7 protein expression, inhibited endogenous TRPM7‐like currents and reduced GBM cellular functions including cell viability, migration and invasion (Wong et al, 2020).…”

Section: Introductionmentioning

confidence: 96%

“…Inhibition of TRPM7 using waixenicin A in GBM cell lines U87 and U251 reduced TRPM7 protein expression, inhibited endogenous TRPM7-like currents and reduced GBM cellular functions including cell viability, migration and invasion (Wong et al, 2020). In mice harbouring GBM xenografts, waixenicin A reduced activity of ki-67, Akt and cofilin while increasing caspase-3 activity (Wong et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of TRPM7 with carvacrol suppresses glioblastoma functions in vivo

Alanazi

Nakatogawa

Wang

et al. 2022

Eur J of Neuroscience

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Glioblastoma (GBM) is the most prevalent and aggressive type of primary human brain tumours originating in the central nervous system. Despite the fact that current treatments involve surgery, chemotherapy (Temozolomide), and radiation therapy, the prognosis for patients diagnosed with GBM remains extremely poor. The standard treatment is not only unable to completely eradicate the tumour cells, but also tumour recurrence after surgical resection presents a major challenge. Furthermore, adjuvant therapies including radiation and chemotherapy have high cytotoxicity which causes extensive damage to surrounding healthy tissues and treatment is usually halted before GBM is fully eradicated. Finally, most GBM cases demonstrate temozolomide resistance, a common reason for GBM treatment failure. Therefore, there is an urgent need to develop a suitable alternative therapy that targets GBM specifically and has low cytotoxicity for healthy cells. We previously reported that transient receptor potential melastatin 7 (TRPM7) channels are aberrantly upregulated in GBM, and inhibition of TRPM7 reduced GBM cellular functions including proliferation, migration, and invasion. This suggests TRPM7 is a potential therapeutic target for GBM treatment. In this study, we investigated the effects of the TRPM7 inhibitor, carvacrol, on human GBM cell lines U87 and U251 in vivo. With the use of a flank xenograft GBM mouse model, we demonstrated that carvacrol significantly reduced the tumour size in both mice injected with U87 and U251 cells, decreased p‐Akt protein level and increased p‐GSK3β protein levels. Therefore, these results suggest that carvacrol may have therapeutic potential for GBM treatment.

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“…For example, the flux of ions such as Ca 2+ and Cl − results in activation of downstream signaling pathways, such as the NF-KB pathway (TMEM16A), Ca 2+ -dependent pathways, and STAT3 and Notch signaling pathways via the transient receptor potential (TRP) family member TRP-melastatin 7 (TRPM7) [ 123 , 124 , 125 ]. Accordingly, it has been shown that pharmacological inhibition of TRPM7 reduces the invasion capacity of U87 cells [ 126 ]. Lastly, it has been reported that acid-sensing ion channels are also overexpressed in glioma cells, which produces acidosis as the tumor cells migrate [ 127 ].…”

Section: Role Of Ion Channels In Glioma Invasionmentioning

confidence: 99%

Tumor Cell Infiltration into the Brain in Glioblastoma: From Mechanisms to Clinical Perspectives

Seker-Polat

Degirmenci

Solaroğlu

et al. 2022

Cancers

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Glioblastoma is the most common and malignant primary brain tumor, defined by its highly aggressive nature. Despite the advances in diagnostic and surgical techniques, and the development of novel therapies in the last decade, the prognosis for glioblastoma is still extremely poor. One major factor for the failure of existing therapeutic approaches is the highly invasive nature of glioblastomas. The extreme infiltrating capacity of tumor cells into the brain parenchyma makes complete surgical removal difficult; glioblastomas almost inevitably recur in a more therapy-resistant state, sometimes at distant sites in the brain. Therefore, there are major efforts to understand the molecular mechanisms underpinning glioblastoma invasion; however, there is no approved therapy directed against the invasive phenotype as of now. Here, we review the major molecular mechanisms of glioblastoma cell invasion, including the routes followed by glioblastoma cells, the interaction of tumor cells within the brain environment and the extracellular matrix components, and the roles of tumor cell adhesion and extracellular matrix remodeling. We also include a perspective of high-throughput approaches utilized to discover novel players for invasion and clinical targeting of invasive glioblastoma cells.

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Inhibition of TRPM7 with waixenicin A reduces glioblastoma cellular functions

Cited by 14 publications

References 46 publications

Mechanisms of Invasion in Glioblastoma: Extracellular Matrix, Ca2+ Signaling, and Glutamate

Mechanisms of Invasion in Glioblastoma: Extracellular Matrix, Ca2+ Signaling, and Glutamate

Inhibition of TRPM7 with carvacrol suppresses glioblastoma functions in vivo

Tumor Cell Infiltration into the Brain in Glioblastoma: From Mechanisms to Clinical Perspectives

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