AMPKα1 deletion in fibroblasts promotes tumorigenesis in athymic nude mice by p52-mediated elevation of erythropoietin and CDK2
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Yanhong Zhou1,2,*, Hairong Xu1,3,*, Ye Ding1, Qiulun Lu1, Ming-Hui Zou1, Ping Song1
1Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA 30303, USA
2Key Laboratory of Hubei Province on Cardio-Cerebral Diseases, Hubei University of Science and Technology, Xianning, Hubei 437100, China
3School of Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, China
*These authors have contributed equally to this work
Ping Song, email: email@example.com
Ming-Hui Zou, email: firstname.lastname@example.org
Keywords: AMPK, p52, erythropoietin, anchorage-independent cell growth, angiogenesis
Received: March 23, 2016 Accepted: July 07, 2016 Published: July 18, 2016
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.
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