Abstract
Glioblastoma, the most common and aggressive type of brain tumors, has devastatingly proliferative and invasive characteristics. The need for finding a novel and specific drug target is urgent as the current approaches have limited therapeutic effects in treating glioblastoma. Xyloketal B is a marine compound obtained from mangrove fungus Xylaria sp. (No. 2508) from the South China Sea, and has displayed antioxidant activity and protective effects on endothelial and neuronal oxidative injuries. In this study, we used a glioblastoma U251 cell line to (1) explore the effects of xyloketal B on cell viability, proliferation, and migration; and (2) investigate the underlying molecular mechanisms and signaling pathways. MTT assay, colony formation, wound healing, western blot, and patch clamp techniques were employed. We found that xyloketal B reduced cell viability, proliferation, and migration of U251 cells. In addition, xyloketal B decreased p-Akt and p-ERK1/2 protein expressions. Furthermore, xyloketal B blocked TRPM7 currents in HEK-293 cells overexpressing TRPM7. These effects were confirmed by using a TRPM7 inhibitor, carvacrol, in a parallel experiment. Our findings indicate that TRPM7-regulated PI3K/Akt and MEK/ERK signaling is involved in anti-proliferation and migration effects of xyloketal B on U251 cells, providing in vitro evidence for the marine compound xyloketal B to be a potential drug for treating glioblastoma.
Highlights
Glioblastoma Multiforme (GBM) is the highest grade glioma tumor and the most malignant form of astrocytoma
We demonstrate that: (1) xyloketal B reduces cell viability, proliferation, and migration of glioblastoma U251 cell lines; (2) xyloketal B downregulates the PI3K/Akt and MAP kinase-extracellular-signal-regulated kinase (ERK) kinase (MEK)/ERK signaling pathways; and (3) xyloketal B blocks the TRPM7 current without altering the
We report that the TRPM7 inhibitor carvacrol can induce effects similar to those of xyloketal B on U251 cells by inhibiting the PI3K/Akt and MER/ERK signaling pathways
Summary
Glioblastoma Multiforme (GBM) is the highest grade glioma (grade IV) tumor and the most malignant form of astrocytoma. Proliferation, survival, and motility of glioblastoma cells are regulated by different intracellular signaling pathways. A large number of genetic abnormalities were uncovered in human glioblastoma samples, and the most prominent one is deregulation of signal transduction pathways [2] It happens in glioblastoma through upregulation or a gain-of-function mutation of receptor tyrosine kinases (RTKs), such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR) [3,4]. These abnormalities cause constitutive activation of Ras/MEK/ERK, PI3K/Akt, and other signal transduction pathways [5].
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