Abstract
Angiogenesis is essential for tumor development. Accumulating evidence suggests that adenosine monophosphate-activated protein kinase (AMPK), an energy sensor and redox modulator, is associated with cancer development. However, the effect of AMPK on tumor development is controversial, and whether AMPK affects tumor angiogenesis has not been resolved. We show that deletion of AMPKα1, but not AMPKα2, upregulates non-canonical nuclear factor kappa B2 (NF-κB2)/p52-mediated cyclin-dependent kinase 2 (CDK2), which is responsible for the anchorage-independent cell growth of immortalized mouse embryo fibroblasts (MEFs). Co-culture with AMPKα1 knockout MEFs (or their conditioned medium) enhances the migration and network formation of human microvascular endothelial cells, which is dependent on p52-upregulated erythropoietin (Epo). AMPKα1 deletion stimulates cellular proliferation of allograft MEFs, angiogenesis, and tumor development in athymic nu/nu mice, which is partly ameliorated by antibody-mediated Epo neutralization. Therefore, the AMPKα1-p52-Epo pathway may be involved in stromal fibroblast-mediated angiogenesis and tumorigenesis.
Highlights
Adenosine monophosphate-activated protein kinase (AMPK) is a heterotrimeric Ser/Thr kinase complex that contains a catalytic subunit (α subunit) and two regulatory subunits (β and γ subunits) [1, 2]
We show that deletion of AMPKa1, but not AMPKa2, upregulates non-canonical nuclear factor kappa B2 (NF-kB2)/p52mediated cyclin-dependent kinase 2 (CDK2), which is responsible for the anchorageindependent cell growth of immortalized mouse embryo fibroblasts (MEFs)
The soft agar assay confirmed that AMPKα1 deletion stimulated anchorage-independent growth (Figure 1B), which is in line with that AMPKα1 silencing rescues melanoma antigen (MAGE)-A3/6RNAi-induced inhibition on colony formation of HeLa cells [23]
Summary
Adenosine monophosphate-activated protein kinase (AMPK) is a heterotrimeric Ser/Thr kinase complex that contains a catalytic subunit (α subunit) and two regulatory subunits (β and γ subunits) [1, 2]. Recent work reported that AMPK activity is required and necessary for kinase suppressor of Ras 2 (KSR2)-mediated transformation and anchorageindependent growth of tumor cells MIN6 and NG108-. Constitutive activation of AMPK induced by loss of the tumor suppressor folliculin is reported to augment hypoxia-induced factor (HIF)-mediated aerobic glycolysis, which is a Warburg metabolic transformation that enhances renal tumorigenesis [7]. Loss of AMPKα1 www.impactjournals.com/oncotarget in B cells accelerates c-Myc-driven lymphomagenesis via HIF-1α-mediated metabolic shift to aerobic glycolysis [11]. These combined results suggest that the reported discrepancy of AMPK function in cancer development may be due to different AMPKα isoforms and different experimental cancer cells and tissue systems. The function of AMPK in cancer biology is not clearly understood, and the role of AMPK in tumor angiogenesis remains unclear
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