Blockage of Cholinergic Signaling via Muscarinic Acetylcholine Receptor 3 Inhibits Tumor Growth in Human Colorectal Adenocarcinoma
| Autor: | Martin E. Kreis, Rayoung Kim, Nina A. Hering, Ioannis Pozios, Marco Arndt, Benjamin Weixler, Verena Liu, Katharina Beyer, Raoul A. Droeser, Hendrik Seeliger |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research Colorectal cancer muscarinic acetylcholine receptor colorectal cancer cholinergic signaling Article 03 medical and health sciences 0302 clinical medicine In vivo Darifenacin Medicine Protein kinase B RC254-282 Tissue microarray business.industry Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease Primary tumor digestive system diseases acetylcholine matrix metalloproteinase 1 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research Immunohistochemistry Cholinergic business darifenacin medicine.drug |
| Zdroj: | Cancers, Vol 13, Iss 3220, p 3220 (2021) Cancers Volume 13 Issue 13 |
| ISSN: | 2072-6694 |
| Popis: | Cholinergic signaling via the muscarinic M3 acetylcholine receptor (M3R) is involved in the development and progression of colorectal cancer (CRC). The present study aimed to analyze the blocking of M3R signaling in CRC using darifenacin, a selective M3R antagonist. Darifenacin effects were studied on HT-29 and SW480 CRC cells using MTT and BrdU assays, Western blotting and real time RT-PCR. In vivo, blocking of M3R was assessed in an orthotopic CRC xenograft BALB/cnu/nu mouse model. M3R expression in clinical tumor specimens was studied by immunohistochemistry on a tissue microarray of 585 CRC patients. In vitro, darifenacin decreased tumor cell survival and proliferation in a dose-dependent manner. Acetylcholine-induced p38, ERK1/2 and Akt signaling, and MMP-1 mRNA expression were decreased by darifenacin, as well as matrigel invasion of tumor cells. In mice, darifenacin reduced primary tumor volume and weight (p < 0.05), as well as liver metastases, compared to controls. High expression scores of M3R were found on 89.2% of clinical CRC samples and correlated with infiltrative tumor border and non-mucinous histology (p < 0.05). In conclusion, darifenacin inhibited components of tumor growth and progression in vitro and reduced tumor growth in vivo. Its target, M3R, was expressed on the majority of CRC. Thus, repurposing darifenacin may be an attractive addition to systemic tumor therapy in CRC patients expressing M3R. |
| Databáze: | OpenAIRE |
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