title: Involvement of Akt2/protein kinase B β (PKBβ) in the 8-Cl-cAMP-induced cancer cell growth inhibition.
abstract: 8-chloro-cyclic AMP (8-Cl-cAMP), which induces differentiation, growth inhibition, and apoptosis in various cancer cells, has been investigated as a putative anti-cancer drug. However, the exact mechanism of 8-Cl-cAMP functioning in cancer cells is not fully understood. Akt/protein kinase B (PKB) genes (Akt1, Akt2, and Akt3) encode enzymes belonging to the serine/threonine-specific protein kinase family. It has been suggested that Akt/PKB enhances cell survival by inhibiting apoptosis. Recently, we showed that 8-Cl-cAMP and 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) inhibited cancer cell growth through the activation of AMPK and p38 MAPK. Therefore, we anticipated that the phosphorylation of Akt/PKB would be decreased upon treatment with 8-Cl-cAMP. However, treatment with 8-Cl-cAMP and AICAR induced the phosphorylation of Akt/PKB, which was inhibited by ABT702 (an adenosine kinase inhibitor) and NBTI (an adenosine transporter inhibitor). Furthermore, whereas Compound C (an AMPK inhibitor), AMPK-DN (AMPK-dominant negative) mutant, and SB203580 (a p38 MAPK inhibitor) did not block the 8-Cl-cAMP-induced phosphorylation of Akt/PKB, TCN (an Akt1/2/3 specific inhibitor) and an Akt2/PKBβ-targeted siRNA inhibited the 8-Cl-cAMP- and AICAR-mediated phosphorylation of AMPK and p38 MAPK. TCN also reversed the growth inhibition mediated by 8-Cl-cAMP and AICAR. Moreover, an Akt1/PKBα-targeted siRNA did not reduce the phosphorylation of AMPK and p38 MAPK after treatment with 8-Cl-cAMP. These results suggest that Akt2/PKBβ activation promotes the phosphorylation of AMPK and p38 MAPK during the 8-Cl-cAMP- and AICAR-induced growth inhibition.
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul, Korea.
authors.forename: Ki Young
authors.initials: KY
authors.lastname: Choi
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Ahn
authors.forename: Hae Won
authors.initials: HW
authors.lastname: Ahn
authors.forename: Young Jun
authors.initials: YJ
authors.lastname: Cho
authors.forename: Seung Hwan
authors.initials: SH
authors.lastname: Hong
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012265:Ribonucleotides / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D012265:Ribonucleotides; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000620:Aminoimidazole Carboxamide; C044258:8-chloro-cyclic adenosine monophosphate; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide