Combined inhibition of DRD2 and Epidermal Growth Factor Receptor (EGFR) led to synergistic tumoricidal activity as well as ERK suppression in independent in vivo and in vitro glioblastoma models.
Consequently, p-mTOR, p-Akt and p-ERK pathways are highly upregulated in the brain tumors, in alignment with their oncogenic activities by CDK4 and PIKE-A stably transfected in GBM cell lines.
Further supporting a role for the p38 MAPK-MK2-HuR pathway in the development of inflammatory environment in GBM, activated MK2 is found in more than 50% of investigated GBM tissues and correlates with lower grade and secondary GBMs.
Furthermore, our data identified MAPK-ERK-YAP signaling pathways as the primary molecular mechanisms by which TNFα modulated mitochondrial fission and glioblastoma apoptosis.
Here we show that ROS-mediated activation of p38 MAPK plays a pivotal role in the control of differentiation and tumor-initiating capacity of glioma-initiating cells (GICs) derived from human glioblastomas.
Importantly, p38 MAPK inhibition strongly reduced invasion of U251 glioblastoma cells in an inflammatory microenvironment, providing evidence for a p38 MAPK-regulated link between inflammation and invasiveness in GBM pathophysiology.
In addition, we detected decreased nuclear localization of Nrf2 following combined treatment with ERK and PI3K inhibitors in three human glioblastoma cell lines and selected the cell line (U251) most sensitive to the inhibitors for further study.
In summary, we have discovered hesperetin as a natural product candidate for the treatment of GBM, and that it could induce GBM cell apoptosis via p38 MAPK activation.
In the current study, we examined the role of JNK- and ERK-dependent signaling modules in the regulation of MMP-9 production and the invasive behavior of the human glioblastoma cell line SNB19, in which JNK/ERK1 is constitutively activated.
Increased expression and activity of p38 MAPK is correlated with poor prognosis in cancer, including glioblastoma multiforme; however, the toxicity of p38 MAPK inhibitors limits their clinical use.
Inhibition experiments of JNK or ERK activities revealed that the ERK pathway strongly promotes cisplatin- and UV-induced apoptosis in these glioblastoma cells.
Interaction network analysis indicated that the GBM-associated proteins in the RNA processing were linked to crucial signaling transduction modulators including epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 1 (STAT1), and mitogen-activated protein kinase 1 (MAPK1), which were further connected to the proteins important for neuronal structural integrity, development and functions.
Kinase-deficient erbB proteins reduced epidermal growth factor (EGF)-induced tyrosine phosphorylation of endogenous Shc proteins and also reduced immediate and sustained EGF-induced ERK MAPK activities in human glioblastoma cells, although basal ERK MAPK activities were unaffected.
Knockdown of EPHA2 and EPHA3 together led to increased expression of differentiation marker GFAP and blocked clonogenic and tumorigenic potential, promoting significantly higher survival <i>in vivo</i> Treatment of rGBM with a bispecific antibody against EPHA2/A3 reduced clonogenicity <i>in vitro</i> and tumorigenic potential of xenografted recurrent GBM <i>in vivo</i> via downregulation of AKT and ERK and increased cellular differentiation.