Inhibition of TRPM7 by carvacrol suppresses glioblastoma cell proliferation, migration and invasion

Abstract

Glioblastomas are progressive brain tumors with devastating proliferative and invasive characteristics. Ion channels are the second largest target class for drug development. In this study, we investigated the effects of the TRPM7 inhibitor carvacrol on the viability, resistance to apoptosis, migration, and invasiveness of the human U87 glioblastoma cell line.The expression levels of TRPM7 mRNA and protein in U87 cells were detected by RT-PCR, western blotting and immunofluorescence. TRPM7 currents were recorded using whole-cell patch-clamp techniques. An MTT assay was used to assess cell viability and proliferation. Wound healing and transwell experiments were used to evaluate cell migration and invasion. Protein levels of p-Akt/t-Akt, p-ERK1/2/t-ERK1/2, cleaved caspase-3, MMP-2 and phosphorylated cofilin were also detected.TRPM7 mRNA and protein expression in U87 cells is higher than in normal human astrocytes. Whole-cell patch-clamp recording showed that carvacrol blocks recombinant TRPM7 current in HEK293 cells and endogenous TRPM7-like current in U87 cells. Carvacrol treatment reduced the viability, migration and invasion of U87 cells. Carvacrol also decreased MMP-2 protein expression and promoted the phosphorylation of cofilin. Furthermore, carvacrol inhibited the Ras/MEK/MAPK and PI3K/Akt signaling pathways.Therefore, carvacrol may have therapeutic potential for the treatment of glioblastomas through its inhibition of TRPM7 channels.

Activation of TRPM7 by naltriben enhances migration and invasion of glioblastoma cells

“…Previously, we reported that the TRPM7 mRNA and protein, as well as channel activity are upregulated in the U87 cells compared to normal human astrocytes [4]. In the current study, we found that naltriben further augmented the TRPM7-like currents in U87 cells.…”

“…Previously, we have shown that pharmacological block or knock-down of TRPM7 inhibited both pathways [4, 5]. In the current study, potentiation of TRPM7 by naltriben upregulated p-ERK1/2 protein levels (Figure 4A, 4C), but not p-Akt levels (Figure 4A, 4F).…”

The Transient Receptor Potential Melastatin 7 Channel Regulates Pancreatic Cancer Cell Invasion through the Hsp90α/uPA/MMP2 pathway

“…Among TRP channels, the transient receptor potential melastatin related 7 (TRPM7) channel is a Ca 2+ /Mg 2+ channel fused with a functional kinase domain that belongs to the α-kinase family [13], [14]. We and others showed that TRPM7 is involved in migration and/or invasion of epidermal cancer cells including neuroblastoma [15], [16], glioblastoma [17], breast cancer [18], [19], nasopharynx cancer [20], [21], lung cancer [22], prostate cancer [23], and PDAC [24], [25]. Importantly, TRPM7 is required for breast cancer metastasis formation in mouse xenograft, and high channel expression is an independent marker of poor outcome in breast cancer patients [26].…”

Kukoamine A inhibits human glioblastoma cell growth and migration through apoptosis induction and epithelial-mesenchymal transition attenuation

“…Glioblastoma (GBM) is the most common malignant primary brain tumor with devastating proliferative and invasive characteristics; its aggressive growth pattern led GBM patients face a poor prognosis even after having received the best available treatment modalities12342829. However, the distinct biological behavior of aggressive proliferation and invasive growth of GBM might be the unexplored therapeutic targets for treatment of this fatal tumor5.…”

“…However, the distinct biological behavior of aggressive proliferation and invasive growth of GBM might be the unexplored therapeutic targets for treatment of this fatal tumor5. Thus, the discovery of new and specific chemotherapeutic agents inhibiting proliferation, migration and invasion of GBM cells are regarded as effective strategies to research and develop new drugs for GBM therapeutics101112131428.…”