AICAR induces cyclooxygenase-2 expression through AMP-activated protein kinase-transforming growth factor-β-activated kinase 1-p38 mitogen-activated protein kinase signaling pathway

Chang, Mei-Ying; Ho, Feng-Ming; Wang, Jang-Shiun; Kang, Hao-Cheng; Chang, Yung; Ye, Zhixian; Lin, Wan-Wan

doi:10.1016/j.bcp.2010.06.049

Cited by 42 publications

(37 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In the present study we demonstrated that AICAR increased ROS production, activated JNK and increased cleaved caspase-3 levels thus initiating apoptosis pathways. In contrast to previous reports (28,29), only a marginal, non-significant activation of p38 MAPK was observed. Apparently apoptosis of DU-145 was due to AMPK activation and not to non-specific side effects of AICAR since caspase-3 activation as well as JNK phosphorylation was completely abrogated in presence of the AMPK inhibitor Comp C. The increase in ROS generation was not due to NADPH oxidase activation since the specific inhibitor VAS2870 was without effects.…”

Section: Discussioncontrasting

confidence: 99%

Activation of AMP-kinase by AICAR induces apoptosis of DU-145 prostate cancer cells through generation of reactive oxygen species and activation of c-Jun N-terminal kinase

Sauer

Engel²,

Milosevic³

et al. 2011

Int J Oncol

View full text Add to dashboard Cite

Abstract. The growth of cancer cells is limited by energy supply which is regulated by the energy sensor AMP-kinase (AMPK). Hence, mimicking a low energy state may inhibit cancer growth and may be exploited in anticancer therapies. In the present study, the impact of AMPK activation on cell growth and apoptosis of DU-145 prostate cancer cells was investigated. Incubation with the AMPK activator aminoimidazole carboxamide ribonucleotide (AICAR) dose-dependently inhibited cell growth, activated AMPK, and inhibited mTOR. Furthermore, AICAR treatment activated c-Jun N-terminal kinase (JNK) and caspase-3, thereby initiating apoptosis. Within 60 min of treatment AICAR raised intracellular reactive oxygen species (ROS) which could be abolished in the presence of the free radical scavenger N-(2-mercaptopropionyl)glycin (NMPG), the AMPK inhibitor compound C (Comp C) and the respiratory chain complex I inhibitor rotenone, but not by the NADPH oxidase inhibitor VAS2870. Inhibition of ROS generation abolished AMPK activation by AICAR as well as JNK and caspase-3 activation. Furthermore, AMPK activation, JNK phosphorylation and cleaved caspase-3 upon AICAR treatment were abolished in the presence of Comp C. In summary, our data demonstrate that activation of AMPK by AICAR induces apoptosis of prostate cancer cells by a signaling pathway involving ROS, activation of JNK and cleaved caspase-3.

show abstract

Section: Discussioncontrasting

confidence: 99%

Activation of AMP-kinase by AICAR induces apoptosis of DU-145 prostate cancer cells through generation of reactive oxygen species and activation of c-Jun N-terminal kinase

Sauer

Engel²,

Milosevic³

et al. 2011

Int J Oncol

View full text Add to dashboard Cite

show abstract

“…5 The situation is, however, currently confused as some reports place the AMPK upstream of TAK1 in inflammatory signaling pathways, indicating a more complicated interaction between the kinases. 6,7 Our investigation indicates that the AMPK is a TAK1 substrate in growth factor-stimulated endothelial cells as TAK1 inhibition prevented VEGF-induced phosphorylation of the AMPK, as well as its downstream target acetyl-CoA carboxylase.…”

Section: Discussionmentioning

confidence: 78%

Transforming Growth Factor-β–Activated Kinase 1 Regulates Angiogenesis via AMP-Activated Protein Kinase-α1 and Redox Balance in Endothelial Cells

Zippel

Malik

Frömel

et al. 2013

ATVB

View full text Add to dashboard Cite

Objective— Transforming growth factor-β–activated kinase 1 (TAK1) is a mitogen-activated protein 3-kinase and an AMP-activated protein kinase (AMPK) kinase in some cell types. Although TAK1 −/− mice display defects in developmental vasculogenesis, the role of TAK1 in endothelial cells has not been investigated in detail. Approach and Results— TAK1 downregulation (small interfering RNA) in human endothelial cells attenuated proliferation without inducing apoptosis and diminished endothelial cell migration, as well as tube formation. Cytokine- and vascular endothelial growth factor (VEGF)–induced endothelial cell sprouting in a modified spheroid assay were abrogated by TAK1 downregulation. Moreover, VEGF–induced endothelial sprouting was impaired in aortic rings from mice lacking TAK1 in endothelial cells (TAK ΔEC ). TAK1 inhibition and downregulation also inhibited VEGF–stimulated phosphorylation of several kinases, including AMPK. Proteomic analyses revealed that superoxide dismutase 2 (SOD2) expression was reduced in TAK1-deficient endothelial cells, resulting in attenuated hydrogen peroxide production but increased mitochondrial superoxide production. Endothelial cell SOD2 expression was also attenuated by AMPK inhibition and in endothelial cells from AMPKα1 −/− mice but was unaffected by inhibitors of c-Jun N-terminal kinase, p38, extracellular signal–regulated kinase 1/2, or phosphatidylinositol 3-kinase/Akt. Moreover, the impaired endothelial sprouting from TAK ΔEC aortic rings was abrogated in the presence of polyethylene glycol-SOD, and tube formation was normalized by the overexpression of SOD2. A similar rescue of angiogenesis was observed in polyethylene glycol-SOD–treated aortic rings from mice with endothelial cell–specific deletion of the AMPKα1. Conclusions— These results establish TAK1 as an AMPKα1 kinase that regulates vascular endothelial growth factor–induced and cytokine-induced angiogenesis by modulating SOD2 expression and the superoxide anion:hydrogen peroxide balance.

show abstract

“…The concentration of AMPK agonist AICAR used in this study seems high; however, this dosage of AICAR was commonly used and is comparable to the previous findings focused on the regulation of inflammation by AMPK. [33][34][35][36] To exclude the off-target effects of AICAR, we used metformin and A-769662 as complementary methods of AMPK activation and found a consistent influence of these agents on monocyte adhesion. This contention is supported by our further observations that genetic activation of AMPK by CA-AMPK␣ mimics the protective effects of AICAR.…”

Section: Discussionmentioning

confidence: 99%

AMP-Activated Protein Kinase Suppresses Endothelial Cell Inflammation Through Phosphorylation of Transcriptional Coactivator p300

Zhang

Qiu

Wang

et al. 2011

ATVB

112

View full text Add to dashboard Cite

Objective-Considerable evidence supports the early involvement of monocyte/macrophage recruitment to activated endothelial cells by leukocyte adhesion molecules during atherogenesis. AMP-activated protein kinase (AMPK) is highly expressed in vascular endothelial cells, but its impact on monocyte adhesion and the related mechanisms are not fully understood. The present study was designed to evaluate the impact of and gain mechanistic insight into the signaling coupling AMPK function to the antiinflammatory response. Methods and Results-5-Aminoimidazole-4-carboxamide-1-␤-D-ribonucleotide (AICAR) treatment or overexpression of constitutively active AMPK markedly reduced human monocytic human acute monocytic leukemia cell line-1 cell adhesion and the expression of vascular cell adhesion molecule-1 in tumor necrosis factor-␣-activated human aortic endothelial cells. Furthermore, AICAR or constitutively active AMPK overexpression strongly inhibited the histone acetyltransferase activity of the transcriptional coactivator p300 by phosphorylation of Ser89, which in turn decreased tumor necrosis factor-␣-activated p300-mediated acetylation of nuclear factor-B p65 on Lys221 and reduced the DNA binding activity of nuclear factor-B by inhibiting its recruitment to its target gene promoters. AMPK phosphorylates the transcriptional coactivator p300 via the atypical protein kinase C/. Conclusion-Our findings demonstrate that transcriptional coactivator p300 phosphorylation at Ser89 by AMPK is critical for the therapeutic effect of AMPK and may be a potential target for pharmaceutical intervention in inflammatory diseases such as atherosclerosis. (Arterioscler Thromb Vasc Biol. 2011;31:2897-2908.)

show abstract

AICAR induces cyclooxygenase-2 expression through AMP-activated protein kinase-transforming growth factor-β-activated kinase 1-p38 mitogen-activated protein kinase signaling pathway

Cited by 42 publications

References 45 publications

Activation of AMP-kinase by AICAR induces apoptosis of DU-145 prostate cancer cells through generation of reactive oxygen species and activation of c-Jun N-terminal kinase

Activation of AMP-kinase by AICAR induces apoptosis of DU-145 prostate cancer cells through generation of reactive oxygen species and activation of c-Jun N-terminal kinase

Transforming Growth Factor-β–Activated Kinase 1 Regulates Angiogenesis via AMP-Activated Protein Kinase-α1 and Redox Balance in Endothelial Cells

AMP-Activated Protein Kinase Suppresses Endothelial Cell Inflammation Through Phosphorylation of Transcriptional Coactivator p300

Contact Info

Product

Resources

About