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Aspects of Non-Neuronal Signalling Functions of Acetylcholine in Colorectal Cancer: Roles for the α7nAChR
University of Kalmar, School of Pure and Applied Natural Sciences.
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Place, publisher, year, edition, pages
Kalmar: Högskolan i Kalmar, 2009. , p. 60
Series
Dissertation series / University of Kalmar, Faculty of Natural Science, ISSN 1650-2779 ; 76
Keywords [en]
alpha7 nicotinic acetylcholine receptor, acetylcholine, colorectal cancer, morphine, nicotine, plasminogen activator inhibitor-1, SLURP-1
National Category
Cancer and Oncology
Research subject
Natural Science, Biomedical Sciences
Identifiers
URN: urn:nbn:se:hik:diva-2348ISBN: 978-91-85993-37-6 (print)OAI: oai:DiVA.org:hik-2348DiVA, id: diva2:275196
Public defence
2009-09-25, Falkens hörsal (C305), Nygatan 18B, Kalmar, 09:00 (English)
Opponent
Supervisors
Available from: 2009-11-04 Created: 2009-11-04 Last updated: 2016-03-11Bibliographically approved
List of papers
1. Functional expression of µ-opioid receptors in the human colon cancer cell line, HT-29, and their localization in human colon.
Open this publication in new window or tab >>Functional expression of µ-opioid receptors in the human colon cancer cell line, HT-29, and their localization in human colon.
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2008 (English)In: Digestive Diseases and Sciences, ISSN 0163-2116, E-ISSN 1573-2568, Vol. 53, no 2, p. 461-466Article in journal (Refereed) Published
Abstract [en]

We have investigated the functional expression of μ-opioid receptors (MORs) in the human colon cancer cell line, HT-29. As revealed by immunocytochemistry, immunoreactivity was present in both the cytoplasm and nuclei of the cells. Challenge with morphine for 24 h (1 nM to 1 μM) barely affected cell proliferation, while the secretion of urokinase type plasminogen activator (a protease involved in invasion/metastasis) was markedly augmented by a concentration of 0.1 μM. Human colon cancer tissue from 14 consecutively operated patients was investigated by immunohistochemistry. MORs were found in the nuclei of colonocytes and immune cells of the lamina propria in tumor-free tissue. In tumor tissue, immunoreactivity was found in the membrane and often in the nuclei of tumor cells. The current findings suggest that morphine administration could affect tumor progression by interfering with, for example, invasive properties. Our demonstration of a nuclear expression of the MORs appears to be a novel finding.

National Category
Medical and Health Sciences
Research subject
Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:hik:diva-2321 (URN)10.1007/s10620-007-9897-y (DOI)
Available from: 2009-11-03 Created: 2009-11-02 Last updated: 2017-12-12Bibliographically approved
2. Is acetylcholine an autocrine/paracrine growth factor via the nicotinic α7-receptor subtype in the human colon cancer cell line HT-29?
Open this publication in new window or tab >>Is acetylcholine an autocrine/paracrine growth factor via the nicotinic α7-receptor subtype in the human colon cancer cell line HT-29?
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2009 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 609, no 1-3, p. 27-33Article in journal (Refereed) Published
Abstract [en]

We used immunochemistry to demonstrate expression of acetylcholine's nicotinic α7-receptor subtype in human colon cancer cell line HT-29. Moreover, RT-PCR and immunochemistry showed that choline acetyltransferase and acetylcholine esterase, the enzymes responsible for acetylcholine synthesis and degradation, respectively, localise in HT-29 cells. Bromoacetylcholine bromide, an inhibitor of choline acetyltransferase, significantly attenuated basal cell growth. Our findings suggest that acetylcholine might serve as an autocrine/paracrine–or speculatively, even intracrine–signalling molecule in cell line HT-29, thus contributing to carcinogenesis/cancer progression.

National Category
Medical and Health Sciences
Research subject
Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:hik:diva-2323 (URN)10.1016/j.ejphar.2009.03.002 (DOI)
Available from: 2009-11-03 Created: 2009-11-02 Last updated: 2017-12-12Bibliographically approved
3. Expression of the endogenous, nicotinic acetylcholine receptor ligand, SLURP-1, in human colon cancer.
Open this publication in new window or tab >>Expression of the endogenous, nicotinic acetylcholine receptor ligand, SLURP-1, in human colon cancer.
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2008 (English)In: Autonomic & Autacoid Pharmacology, ISSN 1474-8665, E-ISSN 1474-8673, Vol. 28, no 4, p. 109-116Article in journal (Refereed) Published
Abstract [en]

1. Secreted mammalian Ly-6/urokinase plasminogen activator receptor-related protein-1 (SLURP-1) is a recently discovered endogenous ligand at the alpha7 subunit of the nicotinic acetylcholine receptors. Previous reports have shown that SLURP-1 is expressed in normal human keratinocytes seemingly with a pro-apoptotic function. Conversely, such expression was markedly attenuated in transformed cells and it was suggested that the molecule could convey protection against malignant transformation. 2. In this study, we demonstrated the mRNA expression (by RT-PCR) and protein expression (by Western blotting and immunocytochemistry) of SLURP-1 in the human colon cancer cell line, HT-29. 3. Furthermore, we demonstrated the expression of SLURP-1 (by immunohistochemistry) in tumour cells of human colon cancer tissue, and, to a greater extent, in immune and smooth muscle cells of adjacent, macroscopically tumour-free colon tissue. 4. The current findings suggest that SLURP-1 participates in the regulation of gut immune functions and motility, as well as possibly playing a role in colon carcinogenesis/cancer progression.

National Category
Medical and Health Sciences
Research subject
Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:hik:diva-2322 (URN)10.1111/j.1474-8673.2008.00424.x (DOI)
Available from: 2009-11-03 Created: 2009-11-02 Last updated: 2017-12-12Bibliographically approved
4. Nicotine induced modulation of SLURP-1 expression in human colon cancer cells.
Open this publication in new window or tab >>Nicotine induced modulation of SLURP-1 expression in human colon cancer cells.
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2009 (English)In: Autonomic Neuroscience: Basic & Clinical, ISSN 1566-0702, E-ISSN 1872-7484, Vol. 148, no 1-2, p. 97-100Article in journal (Refereed) Published
Abstract [en]

The secreted mammalian Ly-6⁄urokinase plasminogen activator receptor-related protein-1 (SLURP-1) is an endogenous ligand at the α7 subunit of the nicotinic acetylcholine receptor (nAChR). SLURP-1 has anti-tumourigenic properties. In the current study, we demonstrate that the challenge of HT-29 human colon cancer cells with nicotine for 24 h to increase cell growth via the α7nAChRs, caused a marked reduction of the protein expression of SLURP-1. We suggest that there is an interplay between acetylcholine and SLURP-1 in the HT-29 cells, both molecules serving as autocrine growth controlling ligands at the α7nAChR, where acetylcholine regulates the release of SLURP-1.

National Category
Medical and Health Sciences
Research subject
Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:hik:diva-2324 (URN)10.1016/j.autneu.2009.03.002 (DOI)
Available from: 2009-11-03 Created: 2009-11-02 Last updated: 2017-12-12Bibliographically approved
5. A pharmacological analysis of the cholinergic regulation of urokinase-type plasminogen activator, and plasminogen activator inhibitor-1 secretion in the human colon cancer cell line, HT-29
Open this publication in new window or tab >>A pharmacological analysis of the cholinergic regulation of urokinase-type plasminogen activator, and plasminogen activator inhibitor-1 secretion in the human colon cancer cell line, HT-29
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2010 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 646, no 1-3, p. 22-30Article in journal (Refereed) Published
Abstract [en]

Urokinase-type plasminogen activator (uPA) is an important factor for tumour cell invasion and metastasis. We recently showed that acetylcholine is an autocrine/paracrine growth factor for the human colon cancer cell line, HT-29, in part via the α7 subtype of the nicotinic acetylcholine receptors. In the current study, we investigated whether acetylcholine participates in the regulation of the protein expressions of also uPA and its receptor (uPAR) in the HT-29 cell line. Such were investigated by immunocytochemistry and Western blotting, and quantitation of uPA secretion was undertaken by ELISA. Stimulation of the cells for 24 h with nicotine caused increased uPA secretion with peak effect (78% above the control) occurring at a nicotine concentration of 10 nM. This effect was markedly inhibited by α-Bungarotoxin, thus showing the involvement of α7 nicotinic acetylcholine receptors. Basal uPA secretion was found to be partly dependent on ongoing activation of nicotinic receptors, suggesting tonic production of acetylcholine. Conversely, there was no cholinergic influence on the expression of uPAR. The current findings demonstrate novel aspects of receptor-mediated regulation of tumour metastatic potential via uPA secretion. This may suggest future pharmaceutical strategies in treatment of colorectal cancer.

Keywords
Acetylcholine, Choline acetyltransferase, HT-29 colon cancer cell line, Nicotine, Urokinase-type plasminogen activator, Urokinase-type plasminogen activator receptor
National Category
Pharmacology and Toxicology
Research subject
Natural Science
Identifiers
urn:nbn:se:hik:diva-2325 (URN)10.1016/j.ejphar.2010.08.004 (DOI)
Available from: 2009-11-03 Created: 2009-11-02 Last updated: 2018-01-12Bibliographically approved
6. Is acetylcholine a signaling molecule for human colon cancer progression?
Open this publication in new window or tab >>Is acetylcholine a signaling molecule for human colon cancer progression?
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2011 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 46, no 4, p. 446-455Article in journal (Refereed) Published
Abstract [en]

Objective. Non-neuronal acetylcholine (ACh) has been suggested to be a mediator for the development of various types of cancer. We analyzed a possible role for this molecule in carcinogenesis and/or progression of human colon cancer, in patient biopsies harvested from the colon during surgery. We addressed whether ACh synthesis (by choline acetyltransferase) and/or degradation (by ACh esterase), as well as the expression of the α7-subtype of the nicotinic ACh receptors, and the peptide ligand at the α7 receptors, secreted mammalian Ly6/urokinase-type plasminogen activator receptor-related protein-1, respectively, are deranged in tumor tissue as compared with macroscopically tumor-free colon tissue. Methods. A total of 38 patients were grouped for analysis based on their respective Dukes stage (either Dukes A + B or C + D). A mucosal tissue sample was harvested from macroscopically tumor-free colon tissue (i.e. control tissue), as well as from the tumor, and protein lysates were prepared for quantitative Western blotting. Full-thickness specimens were taken for immunohistochemistry. Results. For all the above named markers, there was a significant difference between control and tumor tissue with regard to protein levels, and there was, in addition, a significant difference in protein levels between the Dukes A + B and C + D groups. Conclusion. The current findings may suggest a role for ACh in colon carcinogenesis/cancer progression; the data obtained could have prognostic and/or therapeutic significance for this disease.

Keywords
Acetylcholine, choline acetyltransferase, colon cancer, nicotinic acetylcholine receptor, SLURP-1
National Category
Cancer and Oncology
Research subject
Natural Science
Identifiers
urn:nbn:se:hik:diva-2326 (URN)10.3109/00365521.2010.539252 (DOI)
Available from: 2009-11-03 Created: 2009-11-02 Last updated: 2017-12-12Bibliographically approved

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