Site-selective 8-Cl-cAMP which causes growth inhibition and differentiation increases DNA (CRE)-binding activity in cancer cells.
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.
Mednieks
M I
MI
Department of Pediatrics, Pritzker School of Medicine, University of Chicago, IL 60637.
Yokozaki
H
H
Merlo
G R
GR
Tortora
G
G
Clair
T
T
Ally
S
S
Tahara
E
E
Cho-Chung
Y S
YS
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
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