8-Cl-cAMP and its metabolite, 8-Cl-adenosine induce growth inhibition in mouse fibroblast DT cells through the same pathways: protein kinase C activation and cyclin B down-regulation.
8-Chloro-cyclic AMP (8-Cl-cAMP) is known to be most effective in inducing growth inhibition and differentiation of a number of cancer cells. Also, its cellular metabolite, 8-Cl-adenosine was shown to induce growth inhibition in a variety of cell lines. However, the signaling mechanism that governs the effects of 8-Cl-cAMP and/or 8-Cl-adenosine is still uncertain and it is not even sure which of the two is the key molecule that induces growth inhibition. In this study using mouse fibroblast DT cells, it was found that adenosine kinase inhibitor and adenosine deaminase could reverse cellular growth inhibition induced by 8-Cl-cAMP and 8-Cl-adenosine. And 8-Cl-cAMP could not induce growth inhibition in the presence of phosphodiesterase (PDE) inhibitor, but 8-Cl-adenosine could. We also found that protein kinase C (PKC) inhibitor could restore this growth inhibition, and both the 8-Cl-cAMP and 8-Cl-adenosine could activate the enzymatic activity of PKC. Besides, after 8-Cl-cAMP and 8-Cl-adenosine treatment, cyclin B was down-regulated and a CDK inhibitor, p27 was up-regulated in a time-dependent manner. These results suggest that it is not 8-Cl-cAMP but 8-Cl-adenosine which induces growth inhibition, and 8-Cl-cAMP must be metabolized to exert this effect. Furthermore, there might exist signaling cascade such as PKC activation and cyclin B down-regulation after 8-Cl-cAMP and 8-Cl-adenosine treatment.
Ahn
Young-Ho
YH
School of Biological Sciences, Seoul National University, Seoul, Korea.
Jung
Joong Mok
JM
Hong
Seung Hwan
SH
D015762:2-Chloroadenosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D019926:Cyclin B / Q000187:drug effects / Q000378:metabolism*; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects*; D051379:Mice; D041681:NIH 3T3 Cells; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D019926:Cyclin B; D004791:Enzyme Inhibitors; D015762:2-Chloroadenosine; D015124:8-Bromo Cyclic Adenosine Monophosphate; C044258:8-chloro-cyclic adenosine monophosphate; D011493:Protein Kinase C; C075440:8-chloroadenosine