Abstract
BackgroundGlioblastoma multiforme, the most aggressive and malignant primary brain tumor, is characterized by rapid growth and extensive infiltration to neighboring normal brain parenchyma. Our previous studies delineated a crosstalk between PI3K/Akt and JNK signaling pathways, and a moderate anti-glioblastoma synergism caused by the combined inhibition of PI3K p110β (PI3Kβ) isoform and JNK. However, this combination strategy is not potent enough. MLK3, an upstream regulator of ERK and JNK, may replace JNK to exert stronger synergism with PI3Kβ.MethodsTo develop a new combination strategy with stronger synergism, the expression pattern and roles of MLK3 in glioblastoma patient’s specimens and cell lines were firstly investigated. Then glioblastoma cells and xenografts in nude mice were treated with the PI3Kβ inhibitor AZD6482 and the MLK3 inhibitor URMC-099 alone or in combination to evaluate their combination effects on tumor cell growth and motility. The combination effects on cytoskeletal structures such as lamellipodia and focal adhesions were also evaluated.ResultsMLK3 protein was overexpressed in both newly diagnosed and relapsing glioblastoma patients’ specimens. Silencing of MLK3 using siRNA duplexes significantly suppressed migration and invasion, but promoted attachment of glioblastoma cells. Combined inhibition of PI3Kβ and MLK3 exhibited synergistic inhibitory effects on glioblastoma cell proliferation, migration and invasion, as well as the formation of lamellipodia and focal adhesions. Furthermore, combination of AZD6482 and URMC-099 effectively decreased glioblastoma xenograft growth in nude mice. Glioblastoma cells treated with this drug combination showed reduced phosphorylation of Akt and ERK, and decreased protein expression of ROCK2 and Zyxin.ConclusionTaken together, combination of AZD6482 and URMC-099 showed strong synergistic anti-tumor effects on glioblastoma in vitro and in vivo. Our findings suggest that combined inhibition of PI3Kβ and MLK3 may serve as an attractive therapeutic approach for glioblastoma multiforme.
Highlights
Glioblastoma multiforme, the most aggressive and malignant primary brain tumor, is characterized by rapid growth and extensive infiltration to neighboring normal brain parenchyma
Our findings suggest that combined inhibition of Phosphatidylinositol 3-kinases (PI3Ks) p110β isoform (PI3Kβ) and MLK3 may serve as an attractive therapeutic approach for glioblastoma multiforme
It reduced the phosphorylation of Akt and extracellular signal-regulated kinase (ERK), and the protein expression of Rho-associated protein kinase 2 (ROCK2) and Zyxin. This drug combination effectively decreased Glioblastoma multiforme (GBM) xenograft growth in nude mice. These results suggested that combined inhibition of PI3Kβ and MLK3 may be a more effective combination strategy for GBM treatment
Summary
Glioblastoma multiforme, the most aggressive and malignant primary brain tumor, is characterized by rapid growth and extensive infiltration to neighboring normal brain parenchyma. Our previous studies delineated a crosstalk between PI3K/Akt and JNK signaling pathways, and a moderate anti-glioblastoma synergism caused by the combined inhibition of PI3K p110β (PI3Kβ) isoform and JNK This combination strategy is not potent enough. Our previous study showed that combination of the selective PI3K p110β isoform (PI3Kβ) inhibitor (TGX-221) and the JNK inhibitor (SP600125) displayed moderate synergistic inhibitory effects on in-vitro GBM cell proliferation, migration and in-vivo xenograft growth [10]. This synergism was not potent enough to inhibit GBM cell invasion, and the tumor suppressive effect was mild. To improve the efficacy of this synergism on GBM, development of more potent combination strategies is urgently needed
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