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Journal of molecular signaling 2010, PMID: 20863384

AMPK-induced activation of Akt by AICAR is mediated by IGF-1R dependent and independent mechanisms in acute lymphoblastic leukemia.

Leclerc, Gilles M; Leclerc, Guy J; Fu, Guilian; Barredo, Julio C

BACKGROUND

Children with Acute Lymphoblastic Leukemia (ALL) diagnosed with resistant phenotypes and those who relapse have a dismal prognosis for cure. In search for novel treatment strategies, we identified the AMP activated protein kinase (AMPK) as a potential drug target based on its effects on cell growth and survival. We have shown previously that AICAR-induced AMPK activation also induced a compensatory survival mechanism via PI3K/Akt signaling.

RESULTS

In the present study, we further investigated the downstream signaling induced by AMPK activation in ALL cells. We found that AICAR-induced AMPK activation resulted in up-regulation of P-Akt (Ser473 and Thr308) and decrease of P-mTOR (Ser2448) expression and downstream signaling. We determined that activation of P-Akt (Thr308) was mediated by AMPK-induced IGF-1R activation via phosphorylation of the insulin receptor substrate-1 (IRS-1) at Ser794. Inhibition of IGF-1R signaling using the tyrosine kinase inhibitor HNMPA(AM)3 resulted in significant decrease in P-IRS-1 (Ser794) and P-Akt (Thr308). Co-treatment of AICAR plus HNMPA(AM)3 prevented AMPK-induced up-regulation of P-Akt (Thr308) but did not alter the activation of P-Akt (Ser473). Inhibition of AMPK using compound-C resulted in decreased P-Akt expression at both residues, suggesting a central role for AMPK in Akt activation. In addition, inhibition of IGF-1R signaling in ALL cells resulted in cell growth arrest and apoptosis. Additional Western blots revealed that P-IGF-1R (Tyr1131) and P-IRS-1 (Ser794) levels were higher in NALM6 (Bp-ALL) than CEM (T-ALL), and found differences in IGF-1R signaling within Bp-ALL cell line models NALM6, REH (TEL-AML1, [t(12;21)]), and SupB15 (BCR-ABL, [t(9;22)]). In these models, higher sensitivity to IGF-1R inhibitors correlated with increased levels of IGF-1R expression. Combined therapy simultaneously targeting IGF-1R, AMPK, Akt, and mTOR pathways resulted in synergistic growth inhibition and cell death.

CONCLUSIONS

Our study demonstrates that AMPK activates Akt through IGF-1R dependent and independent mechanisms. Co-targeting IGF-1R and related downstream metabolic and oncogenic signaling pathways represent a potential strategy for future translation into novel ALL therapies.

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Text Mining Data

Akt → AMPK: " AMPK induced activation of Akt by AICAR is mediated by IGF-1R dependent and independent mechanisms in acute lymphoblastic leukemia "

P-Akt ⊣ AMPK: " We found that AICAR induced AMPK activation resulted in up-regulation of P-Akt ( Ser473 and Thr308 ) and decrease of P-mTOR ( Ser2448 ) expression and downstream signaling "

P-mTOR ⊣ AMPK: " We found that AICAR induced AMPK activation resulted in up-regulation of P-Akt ( Ser473 and Thr308 ) and decrease of P-mTOR ( Ser2448 ) expression and downstream signaling "

P-Akt → IGF-1R: " We determined that activation of P-Akt ( Thr308 ) was mediated by AMPK induced IGF-1R activation via phosphorylation of the insulin receptor substrate-1 (IRS-1) at Ser794 "

P-Akt → AMPK: " We determined that activation of P-Akt ( Thr308 ) was mediated by AMPK induced IGF-1R activation via phosphorylation of the insulin receptor substrate-1 (IRS-1) at Ser794 "

IGF-1R → AMPK: " We determined that activation of P-Akt ( Thr308 ) was mediated by AMPK induced IGF-1R activation via phosphorylation of the insulin receptor substrate-1 (IRS-1) at Ser794 "

P-Akt ⊣ IGF-1R: " Inhibition of IGF-1R signaling using the tyrosine kinase inhibitor HNMPA ( AM ) 3 resulted in significant decrease in P-IRS-1 ( Ser794 ) and P-Akt ( Thr308 ) "

P-IRS-1 ⊣ IGF-1R: " Inhibition of IGF-1R signaling using the tyrosine kinase inhibitor HNMPA ( AM ) 3 resulted in significant decrease in P-IRS-1 ( Ser794 ) and P-Akt ( Thr308 ) "

P-Akt → AMPK: " Co-treatment of AICAR plus HNMPA ( AM ) 3 prevented AMPK induced up-regulation of P-Akt ( Thr308 ) but did not alter the activation of P-Akt ( Ser473 ) "

Akt ⊣ AMPK: " Inhibition of AMPK using compound-C resulted in decreased P-Akt expression at both residues, suggesting a central role for AMPK in Akt activation "

Manually curated Databases

No curated data.