Involvement of Akt2/protein kinase B b (PKBb) in the 8-Cl-cAMP-Induced Cancer Cell Growth Inhibition
KI YOUNG CHOI, YOUNG HO AHN, HAE WON AHN, YOUNG JUN CHO AND SEUNG HWAN HONG
Journal of Cellular Physiology (228), 890-902 (2013)
|Date||2013 / 1||Type||International Journals|
|File||최기영 J Cell Physiol 2013.pdf (976 KB)|
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 (AMPKdominant 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/PKBb-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/PKBatargeted siRNA did not reduce the phosphorylation of AMPK and p38 MAPK after treatment with 8-Cl-cAMP. These results suggest that Akt2/PKBb activation promotes the phosphorylation of AMPK and p38 MAPK during the 8-Cl-cAMP- and AICAR-induced growth