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This dissertation, Characterization of Melatonin Receptors in Human Placental Trophoblasts and Prostate Cancer by Kai-wing, Lau, 劉啓榮, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled Characterization of melatonin receptors in human placental trophoblasts and prostate cancer Submitted by Kai Wing LAU for the degree of Master of Philosophy at The University of Hong Kong in October 2002 Previous studies have shown that the direct anti-proliferative signals of melatonin, a pineal gland neurohormone, could be transduced, in part, via MT melatonin receptor subtype in placental choriocarcinoma JAr and possibly JEG-3 cells, and via MT receptor subtype in human prostate cancer LNCaP cells. In this study, human MT and MT 1 2 melatonin receptors were expressed in 3A-Sub-E, a post-crisis SV40-transformed human placental trophoblast cell line previously found to express neither receptor subtypes, and 125 were characterized by radioligand binding using 2-[ I]iodomelatonin. The effects of melatonin or 2-iodomelatonin (a melatonin membrane receptor agonist) on the proliferation of 3A-Sub-E cells stably expressing either MT or MT membrane receptors 1 2 were also examined. Furthermore, melatonin receptors in human prostate cancer tissue 125 were characterized by 2-[ I]iodomelatonin binding. Both melatonin and 2-iodomelatonin inhibited JAr cell proliferation. The proliferation of JEG-3 cells was inhibited by melatonin but not by 2-iodomelatonin. These results indicated that MT receptor subtype contributed to the transduction of melatonin anti-proliferative signal in JAr cells, but not in JEG-3 cells. Both MT and MT 1 2 receptor subtypes expressed in transfected 3A-Sub-E cells were saturable and of high 125 125 affinity as assayed by 2-[ I]iodomelatonin binding. Moreover, 2-[ I]iodomelatonin binding to 3A-Sub-E-MT and 3A-Sub-E-MT cells was sensitive to GTPγS and pertussis 1 2 toxin, indicating coupling of both receptor subtypes to G proteins. Pharmacological i/o profiles of MT and MT receptor subtypes constructed from competition curves using 1 2 melatonergic compounds were highly comparable to those reported for other transfectedcells or native tissues. Disappointingly, physiological and pharmacological concentrations of melatonin did not inhibit the proliferation of both 3A-Sub-E-MT and 3A-Sub-E-MT cells. The data suggested that expression of melatonin receptors alone in 2 3A-Sub-E cells did not confer sensitivity to melatonin anti-proliferation, even the receptors demonstrated similar pharmacological properties to endogenous receptors. 125 Notably, melatonin receptors were detected by 2-[ I]iodomelatonin binding in the membrane preparations of a human prostate cancer sample. Saturation study revealed a single class of high-affinity binding sites. Pharmacological profile of the melatonin receptors in the cancer sample was clearly more comparable to those of MT than to MT 1 2 receptors expressed in transfected 3A-Sub-E or PC-3 cells. The expression of MT receptor protein in prostate cancer tissue was further confirmed by immunohistochemistry using anti-MT receptor serum. As MT receptor has been shown 1 1 to play a significant role in transducing the direct anti-proliferative actions of melatonin on human prostate cancer LNCaP cells, expression of MT receptors that can bind to melatonin in the human tissue studied indicates that the prostate cancer cells in this particular patient are very likely to respond to the oncostatic actions of melatonin. Given that melatonin has been reported to inhibit th

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