AMPAR receptor inhibitors suppress proliferation of human small cell lung cancer cell lines

Abstract

BackgroundSmall cell lung cancer (SCLC) is a neuroendocrine tumor with poor prognosis. Neuroendocrine tumors possess characteristics of both nerve cells and hormone‐secreting cells; therefore, targeting the neuronal properties of these tumors may lead to the development of new therapeutic options. Among the endogenous signaling pathways in the nervous system, targeting the glutamate pathway may be a useful strategy for glioblastoma treatment. Perampanel, an antagonist of the synaptic glutamate α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid receptor (AMPAR), has been reported to be effective in patients with glioblastoma. In this study, we aimed to investigate the antitumor effects of AMPAR antagonists in human SCLC cell lines.MethodsWe performed to examine the expression of AMPAR using Western blot and immunohistochemical analysis. The antitumor effects of AMPAR antagonists on human SCLC cell lines were investigated in vitro and in vivo. We also analyzed the signaling pathway of AMPAR antagonists in SCLC cell lines. Statistical analysis was performed by the GraphPad Prism 6 software.ResultsWe first examined the expression of endogenous AMPAR in six human SCLC cell lines, detecting AMPAR proteins in all of them. Next, we tested the anti−proliferative effect of two AMPAR antagonists, talampanel and cyanquixaline, using SCLC cells in vitro and in vivo. Both AMPAR antagonists inhibited cell proliferation and mitogen‐activated protein kinase (MAPK) phosphorylation in SCLC cells in vitro. Further, we observed reduced proliferation of implanted cell lines in an in vivo setting, assessed by Ki‐67 immunohistochemistry. Additionally, using immunohistochemical analysis we confirmed AMPAR protein expression in human SCLC samples.ConclusionAMPAR may be a potential therapeutic target for SCLC.

Expression and role of CNIH2 in prostate cancer

“…It has been reported that, when activated by glutamate, AMPARs promote the invasion and migration of pancreatic cancer cells through the Kras-MAPK signaling pathway 24 . Moreover, AMPARs are expressed in six different small-cell lung cancer cell lines, and the inhibition of AMPARs, either in vivo or in vitro, results in suppressed cell proliferation and reduced MAPK phosphorylation 25 . In glioblastoma, AMPARs expressed in glioblastoma cells promote tumor cell proliferation and migration via beta1 integrin-dependent adhesion to the extracellular matrix 26 .…”

Optimizing perampanel monotherapy for surgically resected brain tumors

“…The expression of GRIA2 and GRIA4 , which encode separate subunits of the AMPA receptor, is upregulated in certain brain tumors besides gliomas ( 43 , 44 ). AMPA receptor inhibitors exhibit antitumor effects in small-cell lung cancer, but not in the brain microenvironment ( 45 ). GRIA2 upregulation has also been detected in melanoma brain metastases ( 46 ).…”