ArticleAmerican journal of physiology. Gastrointestinal and liver physiology2009
Acetylcholine-induced activation of M3 muscarinic receptors stimulates robust matrix metalloproteinase gene expression in human colon cancer cells.
Article in American journal of physiology. Gastrointestinal and liver physiology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
58 citing papers in PubMed, 84 citations in OpenAlex.
- Cancer Neuroscience: From Local Neuro-Immune Microenvironments to Systemic Brain-Body Circuitry.MedComm · 2026Review
- The gut microbiota-enteric nervous system axis: from bidirectional programming to precision therapeutics in digestive diseases.Frontiers in cellular and infection microbiology · 2026Review
- Neurotransmitters and Immunity: Molecular Mechanisms, Biological Functions, Diseases, and Potential Therapeutic Targets.MedComm · 2025Review
- The role of acetylcholine and its receptors in tumor immune regulation: mechanisms and potential therapeutic targets.Molecular cancer · 2025Review
- The function of metalloproteinases in pathophysiology of inflammatory bowel disease and colon cancer.Journal of leukocyte biology · 2025Review
- Neural influences in colorectal cancer progression and therapeutic strategies.International journal of colorectal disease · 2025Review
- The Neuroimmune Axis and Its Therapeutic Potential for Primary Liver Cancer.International journal of molecular sciences · 2024Review
- Article
- Muscarinic receptor agonist-induced βPix binding to β-catenin promotes colon neoplasia.Scientific reports · 2023Article
- The association between prescription drugs and colorectal cancer prognosis: a nationwide cohort study using a medication-wide association study.BMC cancer · 2023Article
- Matrix metalloproteinases as biomarkers and therapeutic targets in colitis-associated cancer.Frontiers in oncology · 2023Review
- Blocking Muscarinic Receptor 3 Attenuates Tumor Growth and Decreases Immunosuppressive and Cholinergic Markers in an Orthotopic Mouse Model of Colorectal Cancer.International journal of molecular sciences · 2022Article
- Nerves in gastrointestinal cancer: from mechanism to modulations.Nature reviews. Gastroenterology & hepatology · 2022Review
- Review
- Muscarinic Receptors Associated with Cancer.Cancers · 2022Review
- Zinc finger protein 277 is an intestinal transit-amplifying cell marker and colon cancer oncogene.JCI insight · 2022Article
- Article
- Mechanistic Clues Provided by Concurrent Changes in the Expression of Genes Encoding the MFrontiers in physiology · 2022Article
- Insights into the Role of Matrix Metalloproteinases in Precancerous Conditions and in Colorectal Cancer.Cancers · 2021Review
- Differential Actions of Muscarinic Receptor Subtypes in Gastric, Pancreatic, and Colon Cancer.International journal of molecular sciences · 2021Review
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Previously, we showed that ACh-induced proliferation of human colon cancer cells is mediated by transactivation of epidermal growth factor (EGF) receptors (EGFRs). In the present study, we elucidate the molecular mechanism underlying this action. ACh-induced proliferation of H508 colon cancer cells, which express exclusively M3 muscarinic receptors (M3Rs), was attenuated by anti-EGFR ligand binding domain antibody, a broad-spectrum matrix metalloproteinase (MMP) inhibitor, anti-MMP7 antibody, a diphtheria toxin analog that blocks release of an EGFR ligand [heparin-binding EGF-like growth factor (HBEGF)], and anti-HBEGF antibody. Conditioned media from ACh-treated H508 cells induced proliferation of SNU-C4 colon cancer cells that express EGFR but not M3R. These actions were attenuated by an EGFR inhibitor and by anti-EGFR and anti-HBEGF antibodies. In H508, but not SNU-C4, colon cancer cells, ACh caused a striking dose- and time-dependent increase in levels of MMP7 mRNA and MMP7 protein. Similarly, ACh induced robust MMP1 and MMP10 gene transcription. ACh-induced MMP1, MMP7, and MMP10 gene transcription was attenuated by atropine, anti-EGFR antibody, and chemical inhibitors of EGFR and ERK activation. In contrast, inhibitors of phosphatidylinositol 3-kinase and NF-kappaB activation did not alter MMP gene transcription. Collectively, these findings indicate that MMP7-catalyzed release of HBEGF mediates ACh-induced transactivation of EGFR and consequent proliferation of colon cancer cells. ACh-induced activation of EGFR and downstream ERK signaling also regulates transcriptional activation of MMP7, thereby identifying a novel feed-forward mechanism for neoplastic cell proliferation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.