Muscarinic receptor signaling and colon cancer progression

Xie, Guofeng; Raufman, Jean‐Pierre

doi:10.20517/2394-4722.2016.05

Cited by 11 publications

(6 citation statements)

References 45 publications

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“…In a clinical context, perineural invasion (PNI) has been identified as a risk factor for poor prognosis in CRC and other gastrointestinal cancers [19,20]. On the other hand, parasympathetic input by ACh via its muscarinic receptor M3R contributes relevantly to CRC carcinogenesis and progression [13,21]. Indeed our in vitro and TMA experiments, in line with recent data, show that cytoplasmic and membrane M3R expression are present in CRC.…”

Section: Discussionsupporting

confidence: 85%

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

Hering

Liu

Kim

et al. 2021

Cancers

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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.

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Section: Discussionsupporting

confidence: 85%

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

Hering

Liu

Kim

et al. 2021

Cancers

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“…These findings are surprising and stand in contrast to the previously reported in vitro and in vivo effects of M3R expression and inhibition [20,[26][27][28][29][30]. Other examples of a strong inverse correlation between tumor grade and receptor expression are described in the literature, for example, numerous studies concerning breast cancer tumor grade and hormone receptor intensity [31][32][33][34], and in astrocytomas, estrogen receptor expression was positive only in low-grade and nil in high-grade astrocytomas [35].…”

Section: Correlation With Previous Literaturementioning

confidence: 76%

Muscarinic Acetylcholine Receptor M3 Expression and Survival in Human Colorectal Carcinoma—An Unexpected Correlation to Guide Future Treatment?

Lobbes

Schütze

Droeser³

et al. 2023

IJMS

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Muscarinic acetylcholine receptor M3 (M3R) has repeatedly been shown to be prominently expressed in human colorectal cancer (CRC), playing roles in proliferation and cell invasion. Its therapeutic targetability has been suggested in vitro and in animal models. We aimed to investigate the clinical role of MR3 expression in CRC for human survival. Surgical tissue samples from 754 CRC patients were analyzed for high or low immunohistochemical M3R expression on a clinically annotated tissue microarray (TMA). Immunohistochemical analysis was performed for established immune cell markers (CD8, TIA-1, FOXP3, IL 17, CD16 and OX 40). We used Kaplan–Meier curves to evaluate patients’ survival and multivariate Cox regression analysis to evaluate prognostic significance. High M3R expression was associated with increased survival in multivariate (hazard ratio (HR) = 0.52; 95% CI = 0.35–0.78; p = 0.001) analysis, as was TIA-1 expression (HR = 0.99; 95% CI = 0.94–0.99; p = 0.014). Tumors with high M3R expression were significantly more likely to be grade 2 compared to tumors with low M3R expression (85.7% vs. 67.1%, p = 0.002). The 5-year survival analysis showed a trend of a higher survival rate in patients with high M3R expression (46%) than patients with low M3R expression CRC (42%) (p = 0.073). In contrast to previous in vitro and animal model findings, this study demonstrates an increased survival for CRC patients with high M3R expression. This evidence is highly relevant for translation of basic research findings into clinically efficient treatments.

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“…CFTR encodes the cystic fibrosis transmembrane conductance regulator, which regulates Cl − secretion ( Borowitz 2015 ). CHRM3 is a muscarinic receptor primarily expressed in gastrointestinal tract and regulate the secretion of gastric acid in parietal cells ( Xie and Raufman 2016 ). ATP4B , encodes the β subunit (H/Kβ) of the gastric proton pump, the heterodimeric gastric H+/K+ ATPase, which transport H + into the GI tract ( Nguyen et al 2004 ).…”

Section: Resultsmentioning

confidence: 99%

Vulture Genomes Reveal Molecular Adaptations Underlying Obligate Scavenging and Low Levels of Genetic Diversity

Zou

Tian

Zhang

et al. 2021

Molecular Biology and Evolution

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Obligate scavenging on dead and decaying animal matter is a rare dietary specialization that in extant vertebrates is restricted to vultures. These birds perform essential ecological services, yet many vulture species have undergone recent steep population declines and are now endangered. To test for molecular adaptations underlying obligate scavenging in vultures, and to assess whether genomic features might have contributed to their population declines, we generated high-quality genomes of the Himalayan and bearded vultures, representing both independent origins of scavenging within the Accipitridae, alongside a sister taxon, the upland buzzard. By comparing our data to published sequences from other birds, we show that the evolution of obligate scavenging in vultures has been accompanied by widespread positive selection acting on genes underlying gastric acid production, and immunity. Moreover, we find evidence of parallel molecular evolution, with amino acid replacements shared among divergent lineages of these scavengers. Our genome-wide screens also reveal that both the Himalayan and bearded vultures exhibit low levels of genetic diversity, equating to around a half of the mean genetic diversity of other bird genomes examined. However, demographic reconstructions indicate that population declines began at around the Last Glacial Maximum, predating the well-documented dramatic declines of the past three decades. Taken together, our genomic analyses imply that vultures harbour unique adaptations for processing carrion, but that modern populations are genetically depauperate and thus especially vulnerable to further genetic erosion through anthropogenic activities.

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Muscarinic receptor signaling and colon cancer progression

Cited by 11 publications

References 45 publications

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

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

Muscarinic Acetylcholine Receptor M3 Expression and Survival in Human Colorectal Carcinoma—An Unexpected Correlation to Guide Future Treatment?

Vulture Genomes Reveal Molecular Adaptations Underlying Obligate Scavenging and Low Levels of Genetic Diversity

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