Tumor-suppressor function of muscarinic acetylcholine receptors is associated with activation of receptor-operated calcium influx.
Several members of the family of guanine nucleotide-binding protein (G protein)-coupled receptors have recently been shown to induce agonist-dependent foci development in NIH 3T3 cells and tumors in nude mice. We selected the five subtypes of the muscarinic acetylcholine receptor family to investigate their role in tumor suppression. When transfected and expressed in CHO-K1 Chinese hamster ovary cells, m1, m3, and m5 muscarinic acetylcholine receptor activation resulted in a morphology change. Receptor activation did not slow or inhibit monolayer growth of CHOm5 cells in culture but markedly inhibited density-independent growth in soft agar and suppressed tumor formation in nude mice. Receptor-mediated tumor suppression was found to be agonist-dependent and reversible and was blocked with a muscarinic receptor antagonist. Of the five signaling pathways associated with the m1, m3, and m5 receptors, only receptor-operated, and inositol trisphosphate-independent, calcium influx was found to correlate with inhibition of tumorigenicity. These data suggest a pivotal role for inositol trisphosphate-independent receptor-regulated calcium homeostasis in CHO-K1 tumor suppression.
Felder
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Laboratory of Cell Biology, National Institute of Mental Health, Bethesda, MD 20892.
MacArthur
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Ma
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Gusovsky
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Kohn
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D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000502:physiology*; D015220:Calcium Channels / Q000502:physiology*; D002217:Carbachol / Q000494:pharmacology; D006224:Cricetinae; D005260:Female; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000473:pathology / Q000503:physiopathology; D010750:Phosphoproteins / Q000378:metabolism; D019000:Phosphotyrosine; D051381:Rats; D011976:Receptors, Muscarinic / Q000502:physiology*; D015290:Second Messenger Systems; D014162:Transfection; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D015220:Calcium Channels; D010750:Phosphoproteins; D011976:Receptors, Muscarinic; D019000:Phosphotyrosine; D014443:Tyrosine; D002217:Carbachol; D002118:Calcium