Involvement of AMP‐activated protein kinase and p38 mitogen‐activated protein kinase in 8‐Cl‐cAMP‐induced growth inhibition

Abstract

8-Cl-cAMP (8-chloro-cyclic AMP), which induces differentiation, growth inhibition and apoptosis in various cancer cells, has been investigated as a putative anti-cancer drug. Although we reported that 8-Cl-cAMP induces growth inhibition via p38 mitogen-activated protein kinase (MAPK) and a metabolite of 8-Cl-cAMP, 8-Cl-adenosine mediates this process, the action mechanism of 8-Cl-cAMP is still uncertain. In this study, it was found that 8-Cl-cAMP-induced growth inhibition is mediated by AMP-activated protein kinase (AMPK). 8-Cl-cAMP was shown to activate AMPK, which was also dependent on the metabolic degradation of 8-Cl-cAMP. A potent agonist of AMPK, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) could also induce growth inhibition and apoptosis. To further delineate the role of AMPK in 8-Cl-cAMP-induced growth inhibition and apoptosis, we used two approaches: pharmacological inhibition of the enzyme with compound C and expression of a dominant negative mutant (a kinase-dead form of AMPKalpha2, KD-AMPK). AICAR was able to activate p38 MAPK and pre-treatment with AMPK inhibitor or expression of KD-AMPK blocked this p38 MAPK activation. Cell growth inhibition was also attenuated. Furthermore, p38 MAPK inhibitor attenuated 8-Cl-cAMP- or AICAR-induced growth inhibition but had no effect on AMPK activation. These results demonstrate that 8-Cl-cAMP induced growth inhibition through AMPK activation and p38 MAPK acts downstream of AMPK in this signaling pathway.

SHC1 sensitizes cancer cells to the 8-Cl-cAMP treatment

“…1B and C). As published earlier [8,9], 8-Cl-cAMP increased the phosphorylation of AMPK and p38 MAPK in these cells ( Fig. 1B and C).…”

“…Previously, we showed that AMPK and p38 MAPK are essential factors for 8-Cl-cAMP-induced growth inhibition [8,9]. In this study, we revealed that p38 MAPK interacts with SHC1 (Fig.…”

Compound C induces protective autophagy in cancer cells through AMPK inhibition-independent blockade of Akt/mTOR pathway

“…29 In addition, compound C inhibited pro-apoptotic and anti-apoptotic actions of AMPK in various experimental settings 18,24,25,[30][31][32][33][34][35][36] and blocked AMPK-dependent autophagy in different types of normal and cancer cells. 25,[37][38][39] In the present study, contrary to expectations, we demonstrate for the first time the ability of compound C to induce autophagic response in different cancer cell lines.…”

8-Chloroadenosine 3′,5′-monophosphate induces cell cycle arrest and apoptosis in multiple myeloma cells through multiple mechanisms

“…Thus, on the basis of the above results, p27 is functionally linked to the sensitivity of the RPMI-8226 cells to 8-Cl-cAMP-induced apoptosis. (15,21). Therefore, we evaluated the effect of 8-Cl-cAMP on p38 MAPK phosphorylation in the MM cells.…”

“…8-Cl-cAMP is a site-selective analog of cAMP. It has been reported that 8-Cl-cAMP shows a potent growth inhibitory effect and has reverse-transforming activity in cancer cells (15)(16)(17)(18). In the current study, we investigated the ability of 8-Cl-cAMP to induce apoptosis in two MM cell lines, RPMI-8226 and U266.…”