Alpha5 nicotine acetylcholine receptor subunit promotes intrahepatic cholangiocarcinoma metastasis

• Published in: Signal transduction and targeted therapy 2024-03, Vol.9 (1), p.63-63, Article 63
• Main Authors: Fu, Yan, Shen, Keyu, Wang, Hao, Wang, Shun, Wang, Xufeng, Zhu, Le, Zheng, Yan, Zou, Tiantian, Ci, Hongfei, Dong, Qiongzhu, Qin, Lun-Xiu
• Format: Article
• Language: English
• Subjects: 631/67/322; 692/4028/67/1504; Acetylcholine; Acetylcholine receptors; Addictions; Axonogenesis; Benzenesulfonamides; Benzylamines; beta Catenin - metabolism; Bile Duct Neoplasms - drug therapy; Bile Duct Neoplasms - genetics; Bile Duct Neoplasms - metabolism; Bile Ducts, Intrahepatic - metabolism; Bile Ducts, Intrahepatic - pathology; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - genetics; Ca2+/calmodulin-dependent protein kinase II; Calcium influx; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics; Calmodulin; Cancer Research; Cancer therapies; Cell Biology; Cell Line, Tumor; Cholangiocarcinoma; Cholangiocarcinoma - drug therapy; Cholangiocarcinoma - genetics; Enzyme-linked immunosorbent assay; Gemcitabine; Glycogen Synthase Kinase 3 beta; Humans; Immunofluorescence; Internal Medicine; Kinases; Medicine; Medicine & Public Health; Metastases; Metastasis; Nerve growth factor; Neurotransmitter Agents; Neurotransmitters; Nicotine; Oncology; Pathology; Phenotypes; Receptors, Cholinergic; Signal transduction; Tumor cells; Tumor Microenvironment; Tumors; β-Catenin
• ISSN: 2059-3635; 2095-9907; 2059-3635
• DOI: 10.1038/s41392-024-01761-z

Neurotransmitter-initiated signaling pathway were reported to play an important role in regulating the malignant phenotype of tumor cells. Cancer cells could exhibit a “neural addiction” property and build up local nerve networks to achieve an enhanced neurotransmitter-initiated signaling through nerve growth factor-mediated axonogenesis. Targeting the dysregulated nervous systems might represent a novel strategy for cancer treatment. However, whether intrahepatic cholangiocarcinoma (ICC) could build its own nerve networks and the role of neurotransmitters in the progression ICC remains largely unknown. Immunofluorescence staining and Enzyme-linked immunosorbent assay suggested that ICC cells and the infiltrated nerves could generate a tumor microenvironment rich in acetylcholine that promotes ICC metastasis by inducing epithelial-mesenchymal transition (EMT). Acetylcholine promoted ICC metastasis through interacting with its receptor, alpha 5 nicotine acetylcholine receptor subunits (CHRNA5). Furthermore, acetylcholine/CHRNA5 axis activated GSK3β/β-catenin signaling pathway partially through the influx of Ca 2+ -mediated activation of Ca/calmodulin-dependent protein kinases (CAMKII). In addition, acetylcholine signaling activation also expanded nerve infiltration through increasing the expression of Brain-Derived Neurotrophic Factor (BDNF), which formed a feedforward acetylcholine-BDNF axis to promote ICC progression. KN93, a small-molecule inhibitor of CAMKII, significantly inhibited the migration and enhanced the sensitivity to gemcitabine of ICC cells. Above all, Acetylcholine/CHRNA5 axis increased the expression of β-catenin to promote the metastasis and resistance to gemcitabine of ICC via CAMKII/GSK3β signaling, and the CAMKII inhibitor KN93 may be an effective therapeutic strategy for combating ICC metastasis.