Restoration of adenylate cyclase responsiveness in murine myeloid leukemia permits inhibition of proliferation by hormone. Butyrate augments catalytic activity of adenylate cyclase.
Mechanisms of leukemic cell clonal dominance may include aberrations of transmembrane signaling. In particular, neoplastic transformation has been associated with reduced capacity for hormone-stimulated adenylate cyclase activity. In the present study, prostaglandin E, a hormonal activator of adenylate cyclase that has antiproliferative activity in myeloid cells, and cholera toxin, an adenylate cyclase agonist that functions at a postreceptor site by activating the adenylate cyclase stimulatory GTP-binding protein (Gs), were studied for antiproliferative activity in two murine myeloid cell lines. FDC-P1, an interleukin 3 (IL 3)-dependent myeloid cell line and a tumorigenic IL 3-independent subline, FI, were resistant to these antiproliferative agents. The in vitro ability of the "differentiation" agent, sodium butyrate, to reverse their resistance to adenylate cyclase agonists was studied. The antiproliferative action of butyrate involved augmentation of transmembrane adenylate cyclase activity. Increased adenylate cyclase catalyst activity was the primary alteration of this transmembrane signaling group leading to the functional inhibitory effects on leukemia cells, although alterations in regulatory G-proteins appear to play a secondary role.
D000262:Adenylyl Cyclases / Q000378:metabolism / Q000502:physiology*; D000527:Alprostadil / Q000494:pharmacology*; D000818:Animals; D002087:Butyrates / Q000494:pharmacology*; D020148:Butyric Acid; D002461:Cell Line, Transformed; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D002772:Cholera Toxin / Q000494:pharmacology*; D004357:Drug Synergism; D019204:GTP-Binding Proteins / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology*; D007951:Leukemia, Myeloid / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism
D002087:Butyrates; C029152:G-substrate; D006131:Growth Inhibitors; D009419:Nerve Tissue Proteins; D020148:Butyric Acid; D002772:Cholera Toxin; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D000527:Alprostadil