title: 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.
authors.affiliation: Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA 30303, USA.|Key Laboratory of Hubei Province on Cardio-Cerebral Diseases, Hubei University of Science and Technology, Xianning, Hubei 437100, China.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA 30303, USA.|School of Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, China.
authors.forename: Hairong
authors.initials: H
authors.lastname: Xu
authors.affiliation: Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Qiulun
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Zou
authors.affiliation: Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Song
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D018920:Coculture Techniques; D051357:Cyclin-Dependent Kinase 2 / Q000096:biosynthesis*; D004921:Erythropoietin / Q000096:biosynthesis*; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D052003:NF-kappa B p52 Subunit / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism*
chemical_list: D052003:NF-kappa B p52 Subunit; D004921:Erythropoietin; C548179:Prkaa1 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D055372:AMP-Activated Protein Kinases
keywords: AMPK; anchorage-independent cell growth; angiogenesis; erythropoietin; p52