title: Site-selective 8-Cl-cAMP which causes growth inhibition and differentiation increases DNA (CRE)-binding activity in cancer cells.
abstract: Control mechanisms of normal differentiation are disrupted in cancer cells but can be restored by treatment with site-selective cAMP analogs. The cellular events associated with such changes entail compartmental redistribution of the cAMP-dependent protein kinase type II regulatory subunit, RII beta. The results of this study indicate that the molecular mechanisms of action involve changes in specific DNA-binding activity of putative transcription factors. Gel retardation analyses revealed that nuclear extracts from cells of various human cancer cell lines [colon cancer (LS-174T), gastric cancer (TMK-1), and leukemia (K-562)] and rodent pheochromocytoma (PC12) show a concentration-dependent increase in binding activity to a synthetic DNA that contained the cAMP-responsive element 5'-TGACGTCA-3' after treatment with 8-Cl-cAMP. Such an increase in cAMP-responsive element binding activity was not observed in the 8-C1-cAMP-unresponsive MKN-1 gastric cancer cells. These findings indicate that the antitumor activity of site-selective cAMP analogs may reside in the induction of transcription factors that restore normal gene regulation in cancer cells.
authors.affiliation: Department of Pediatrics, Pritzker School of Medicine, University of Chicago, IL 60637.
authors.forename: M I
authors.initials: MI
authors.lastname: Mednieks
authors.forename: H
authors.initials: H
authors.lastname: Yokozaki
authors.forename: G R
authors.initials: GR
authors.lastname: Merlo
authors.forename: G
authors.initials: G
authors.lastname: Tortora
authors.forename: T
authors.initials: T
authors.lastname: Clair
authors.forename: S
authors.initials: S
authors.lastname: Ally
authors.forename: E
authors.initials: E
authors.lastname: Tahara
authors.forename: Y S
authors.initials: YS
authors.lastname: Cho-Chung
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents; D001665:Binding Sites; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein; D004273:DNA, Neoplasm / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D017362:Cyclic AMP Response Element-Binding Protein; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D015124:8-Bromo Cyclic Adenosine Monophosphate; C044258:8-chloro-cyclic adenosine monophosphate