Suppression of metastasis by mirtazapine via restoration of the Lin-7C/β-catenin pathway in human cancer cells

• DOI: 10.1038/srep05433
• Publication Date: 2014-06-25T09:04:05Z
• Authors: Katsuhiro Uzawa; Atsushi Kasamatsu; Toshihiro Shimizu; Yasuhiro Saito; Takao Baba; Kentaro Sakuma; Kazuaki Fushimi; Yosuke Sakamoto; Katsunori Ogawara; Masashi Shiiba; Hideki Tanzawa
• Keywords: 0301 basic medicine; Mice, Inbred BALB C; Reverse Transcriptase Polymerase Chain Reaction; Immunoblotting; Membrane Proteins; Mice, Nude; Mirtazapine; Mianserin; Xenograft Model Antitumor Assays; Article; 3. Good health; Gene Expression Regulation, Neoplastic; 03 medical and health sciences; Cell Movement; Cell Line, Tumor; Neoplasms; Carcinoma, Squamous Cell; Receptor, Serotonin, 5-HT2C; Animals; Humans; Neoplasm Metastasis; Melanoma; Adrenergic alpha-Antagonists; Signal Transduction

No definitive therapy exists to treat human metastatic tumors. We reported previously that down-regulation of Lin-7C is essential for metastasis of human squamous cell carcinomas (hSCCs). In this study, we investigated the chemical restoration of Lin-7C expression and demonstrated its effectiveness for suppressing the metastatic potential in human cancer cells. Ingenuity Pathway Analysis (IPA) identified candidate chemical agents, i.e., apomorphine, caffeine, risperidone, quetiapine, and mirtazapine. Among them, mirtazapine, an antagonist of HTR2C, an upstream molecule of Lin-7C, caused substantial up-regulation of the Lin-7C/β-catenin pathway in a metastatic hSCC cell line and human melanoma-derived cell line in vitro, and up-regulation did not contribute to cellular proliferation. Moreover, the antimetastatic effect of mirtazapine in these metastatic cell lines in vivo also was evident in multiple organs of immunodeficient mice with no marked side effects. The current data offer novel information for further study of antimetastatic activity in association with enhanced Lin-7C/β-catenin pathway activation with mirtazapine.