title: 8-Chloro-cyclic AMP-induced growth inhibition and apoptosis is mediated by p38 mitogen-activated protein kinase activation in HL60 cells.
abstract: 8-Chloro-cyclic AMP (8-Cl-cAMP), which is known to induce growth inhibition, apoptosis, and differentiation in various cancer cell lines, has been studied as a putative anticancer drug. However, the mechanism of anticancer activities of 8-Cl-cAMP has not been fully understood. Previously, we reported that the 8-Cl-cAMP-induced growth inhibition is mediated by protein kinase C (PKC) activation. In this study, we found that p38 mitogen-activated protein kinase (MAPK) also plays important roles during the 8-Cl-cAMP-induced growth inhibition and apoptosis. SB203580 (a p38-specific inhibitor) recovered the 8-Cl-cAMP-induced growth inhibition and apoptosis, whereas other MAPK inhibitors, such as PD98059 (an extracellular signal-regulated kinase-specific inhibitor) and SP600125 (a c-Jun NH2-terminal kinase-specific inhibitor), had no effect. The phosphorylation (activation) of p38 MAPK was increased in a time-dependent manner after 8-Cl-cAMP treatment. Furthermore, SB203580 was able to block PKC activation induced by 8-Cl-cAMP. However, PKC inhibitor (GF109203x) could not attenuate p38 activation, indicating that p38 MAPK activation is upstream of PKC activation during the 8-Cl-cAMP-induced growth inhibition. 8-Chloro-adenosine, a metabolite of 8-Cl-cAMP, also activated p38 MAPK and this activation was blocked by adenosine kinase inhibitor. These results suggest that 8-Cl-cAMP exerts its anticancer activity through p38 MAPK activation and the metabolite(s) of 8-Cl-cAMP mediates this process.
authors.affiliation: School of Biological Sciences, Institute of Molecular Biology and Genetics, and Interdisciplinary Graduate Program in Genetic Engineering, Seoul National University, Seoul, Korea.
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Ahn
authors.forename: Joong Mok
authors.initials: JM
authors.lastname: Jung
authors.forename: Seung Hwan
authors.initials: SH
authors.lastname: Hong
mesh_terms: D015762:2-Chloroadenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D048708:Cell Growth Processes / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D015762:2-Chloroadenosine; D015124:8-Bromo Cyclic Adenosine Monophosphate; C044258:8-chloro-cyclic adenosine monophosphate; D017868:Cyclic AMP-Dependent Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C075440:8-chloroadenosine