Abstract
The expression and potential biological functions of G protein-coupled receptor kinase 6 (GRK6) in human glioma are tested in this study. We show that protein and mRNA expression of GRK6 in human glioma tissues was significantly higher than that in the normal brain tissues. Further immunohistochemistry assay analyzing total 118 human glioma tissues showed that GRK6 over-expression was correlated with glioma pathologic grade and patients’ Karnofsky performance status (KPS) score. At the molecular level, in the GRK6-low H4 glioma cells, forced over-expression of GRK6 promoted cell proliferation. Reversely, siRNA-mediated knockdown of GRK6 in the U251MG (GRK6-high) cells led to proliferation inhibition and cell cycle arrest. Intriguingly, GRK6 could also be an important temozolomide resistance factor. Temozolomide-induced cytotoxicity was prominent only in GRK6-low H4 glioma cells. On the other hand, knockdown of GRK6 by targeted siRNA sensitized U251MG cells (GRK6-high) to temozolomide. Thus, GRK6 over-expression in glioma is important for cell proliferation and temozolomide resistance.
Highlights
Glioma is the most common malignant tumor in human brain [1]
We show that protein and mRNA expression of G protein-coupled receptor kinase 6 (GRK6) in human glioma tissues was significantly higher than that in the normal brain tissues
Quantitative results demonstrated that GRK6 expression level was highest in Grade III/IV glioma tissues, but was less higher in grade II glioma tissues
Summary
Glioma is the most common malignant tumor in human brain [1]. The most aggressive subtype of glioma is glioblastoma (GBM), which is the grade IV astrocytic tumor [2]. The prognosis of GBM and other advanced glioma has been poor, and the five-year survival is dismal. This is possibly due to tumor cell extremely high proliferation ability and invasiveness trait [3, 4]. GRKs phosphorylate specific serine and threonine residues in the cytoplasmic domains of the activated receptor, thereby promoting receptor interaction, and uncoupling of the receptor from its G protein [7,8,9]. GRK2 and GRK3 are pleckstrin homology (PH) domain-containing proteins, which are recruited to the membrane by Gβγ upon receptor activation [10, 16]. GRK4, GRK5 and GRK6 are membrane-associated proteins, and are directly activated by the receptor and/or ligand complexes [10, 16]
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