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

Nami Masumoto; Shingo Kato; Masahiro Aichi; Sho Hasegawa; Kota Sahara; Kumiko Suyama; Akane Sano; Tomoyuki Miyazaki; Koji Okudela; Takeshi Kaneko; Takuya Takahashi

doi:10.1111/1759-7714.15075

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

Thorac Cancer. 2023 Oct;14(29):2897-2908. doi: 10.1111/1759-7714.15075. Epub 2023 Aug 22.

Authors

Nami Masumoto^{1

2

3}, Shingo Kato^{4

5}, Masahiro Aichi^{2

6}, Sho Hasegawa⁵, Kota Sahara^{2

7}, Kumiko Suyama², Akane Sano², Tomoyuki Miyazaki^{2

8}, Koji Okudela⁹, Takeshi Kaneko¹, Takuya Takahashi²

Affiliations

¹ Department of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
² Department of Physiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
³ Department of Respirology, National Hospital Organization Yokohama Medical Center, Yokohama, Japan.
⁴ Department of Clinical Cancer Genomics, Yokohama City University Hospital, Yokohama, Japan.
⁵ Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
⁶ Department of Obstetrics, Gynecology and Molecular Reproductive Science, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
⁷ Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
⁸ Center for Promotion of Research and Industry-Academic Collaboration, Department of Core Project Promotion, Yokohama City University, Yokohama, Japan.
⁹ Department of Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Abstract

Background: Small 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.

Methods: We 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.

Results: We 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.

Conclusion: AMPAR may be a potential therapeutic target for SCLC.

Keywords: AMPAR; cyanquixaline; small cell lung cancer; talampanel; α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor.

Abstract

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