AMPKα1 deletion in fibroblasts promotes tumorigenesis in athymic nude mice by p52-mediated elevation of erythropoietin and CDK2

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.

Loss of AMPKalpha1 Triggers Centrosome Amplification via PLK4 Upregulation in Mouse Embryonic Fibroblasts

“…Incorrect chromosome separation would lead to cellular apoptosis or hyperproliferation. p52 knockdown by specific shRNA inhibits the enhanced colony formation of AMPKα1-deleted MEFs [35], suggesting that p52 upregulation plays a critical role in the hyperproliferation of AMPKα1-deleted MEFs. Additionally, AMPKα1 deletion-mediated chromosome missegregation-caused cellular hyperproliferation may be due to p21 reduction, which is consistent with p21 knockout and contributes to the growth of PLK4-overexpressing cells [50].…”

“…Next, we wanted to know the underlying mechanism for PLK4 elevation in AMPKα1 −/− MEFs. Since it was reported that AMPKα1 deletion upregulates nuclear factor-kappa B2/p52 [35], we tested…”

“…Next, we wanted to know the underlying mechanism for PLK4 elevation in AMPKα1 −/− MEFs. Since it was reported that AMPKα1 deletion upregulates nuclear factor-kappa B2/p52 [35], we tested if p52 mediates PLK4 upregulation in AMPKα1 −/− MEFs. As depicted in Figure 4a, p52 knockdown by specific siRNA dramatically blocked the AMPKα1 −/− -upregulated PLK4 mRNA.…”

“…AMPK was demonstrated to localize on centrosomes [32,33]. Emerging data indicate that AMPK plays a vital role in tumor suppression [34][35][36][37][38][39]. However, the precise role of the AMPKα subunit and the mechanism by which AMPK might control accurate chromosome segregation during mitosis remain elusive.…”

AMP‑activated protein kinase α1 serves a carcinogenic role via regulation of vascular endothelial growth factor expression in patients with non‑small cell lung cancer

“…This observation of the aggressive role of AMPK α1 in NSCLC was consistent with previous findings (6,14). However, AMPK α1 has also been indicated as a tumor suppressor (15), and its deletion reportedly promotes cell proliferation and angiogenesis (16). This discrepancy in different cancer types may be the result of different tissue systems, in addition to different targets and associated pathways.…”