title: Hypoxia negatively regulates antimetastatic PEDF in melanoma cells by a hypoxia inducible factor-independent, autophagy dependent mechanism.
abstract: Pigment epithelium-derived factor (PEDF), a member of the serine protease inhibitor (SERPIN) superfamily, displays a potent antiangiogenic and antimetastatic activity in a broad range of tumor types. Melanocytes and low aggressive melanoma cells secrete high levels of PEDF, while its expression is lost in highly aggressive melanomas. PEDF efficiently abrogates a number of functional properties critical for the acquisition of metastatic ability by melanoma cells, such as neovascularization, proliferation, migration, invasiveness and extravasation. In this study, we identify hypoxia as a relevant negative regulator of PEDF in melanocytes and low aggressive melanoma cells. PEDF was regulated at the protein level. Importantly, although downregulation of PEDF was induced by inhibition of 2-oxoglutarate-dependent dioxygenases, it was independent of the hypoxia inducible factor (HIF), a key mediator of the adaptation to hypoxia. Decreased PEDF protein was not mediated by inhibition of translation through untranslated regions (UTRs) in melanoma cells. Degradation by metalloproteinases, implicated on PEDF degradation in retinal pigment epithelial cells, or by the proteasome, was also excluded as regulatory mechanism in melanoma cells. Instead, we found that degradation by autophagy was critical for PEDF downregulation under hypoxia in human melanoma cells. Our findings show that hypoxic conditions encountered during primary melanoma growth downregulate antiangiogenic and antimetastasic PEDF by a posttranslational mechanism involving degradation by autophagy and could therefore contribute to the acquisition of highly metastatic potential characteristic of aggressive melanoma cells.
authors.affiliation: Department of Biochemistry, Universidad Autónoma de Madrid-UAM, Madrid, Spain.
authors.forename: Asunción
authors.initials: A
authors.lastname: Fernández-Barral
authors.forename: José Luis
authors.initials: JL
authors.lastname: Orgaz
authors.forename: Valentí
authors.initials: V
authors.lastname: Gomez
authors.forename: Luis
authors.initials: L
authors.lastname: del Peso
authors.forename: María José
authors.initials: MJ
authors.lastname: Calzada
authors.forename: Benilde
authors.initials: B
authors.lastname: Jiménez
mesh_terms: D001343:Autophagy; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D015687:Cell Hypoxia; D015536:Down-Regulation; D005136:Eye Proteins / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D009362:Neoplasm Metastasis; D009414:Nerve Growth Factors / Q000378:metabolism*; D015843:Serpins / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D020506:Untranslated Regions; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005136:Eye Proteins; D009414:Nerve Growth Factors; D015843:Serpins; D020506:Untranslated Regions; D000099174:Pigment Epithelium-Derived Factor