Blockage of Cholinergic Signaling via Muscarinic Acetylcholine Receptor 3 Inhibits Tumor Growth in Human Colorectal Adenocarcinoma

Cancers

卷:13

Verena Liu¹  Katharina Beyer²  Marco Arndt²  Nina A. Hering²  Benjamin Weixler²  Ioannis Pozios²  Hendrik Seeliger²  Rayoung Kim²  Martin E. Kreis²  Raoul A. Droeser³ 

[1] Department of General Surgery, Vivantes Neukölln Hospital, 12351 Berlin, Germany;

[2] Department of General and Visceral Surgery, Campus Benjamin Franklin, Charité Universitätsmedizin Berlin, 12200 Berlin, Germany;

[3] Department of Visceral Surgery, Clarunis University Center for Gastrointestinal and Liver Disease, St. Clara Hospital and University Hospital Basel, 4002 Basel, Switzerland;

关键词: colorectal cancer;    acetylcholine;    muscarinic acetylcholine receptor;    cholinergic signaling;    darifenacin;    matrix metalloproteinase 1;   

DOI  :  10.3390/cancers13133220

来源: DOAJ

【 摘 要 】

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/c^nu/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.

【 授权许可】

Unknown