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: Ki Young Choi, Young Ho Ahn, Hae Won Ahn, Young Jun Cho, Seung Hwan Hong
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 228 Issue 4 Pg. 890-902 (Apr 2013) ISSN: 1097-4652 [Electronic] United States
• PMID: 23018889 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Wiley Periodicals, Inc.

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Ribonucleotides
• 8-Bromo Cyclic Adenosine Monophosphate
• Aminoimidazole Carboxamide
• 8-chloro-cyclic adenosine monophosphate
• AKT2 protein, human
• Proto-Oncogene Proteins c-akt
• p38 Mitogen-Activated Protein Kinases
• AMP-Activated Protein Kinases
• AICA ribonucleotide

Topics

• 8-Bromo Cyclic Adenosine Monophosphate (analogs & derivatives, pharmacology)
• AMP-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Aminoimidazole Carboxamide (analogs & derivatives, pharmacology)
• Antineoplastic Agents (pharmacology)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• HeLa Cells
• Humans
• MCF-7 Cells
• Neoplasms (drug therapy, metabolism, pathology)
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (pharmacokinetics)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Ribonucleotides (pharmacology)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)