Hypoxia negatively regulates antimetastatic PEDF in melanoma cells by a hypoxia inducible factor-independent, autophagy dependent mechanism
EntityUAM. Departamento de Bioquímica; UAM. Departamento de Medicina
PublisherPublic Library of Science
10.1371/journal.pone.0032989Plos One 7.3 (2012): e32989
Funded byThis work was supported by grants Ministerio de Educacion y Ciencia SAF2007-62292 and SAF2010-19256 to BJ, SAF2009-11113 to MJC and SAF2008- 03147 to LP. AFB was supported by a CSIC-JAE fellowship, JLO by a Ministerio de Educación y Ciencia SAF2007-62292 contract and VG by S-SAL-0311_2006 grant
SubjectsAutophagy; Cell Hypoxia; Melanoma; Tumor Cells; Eye Proteins; Medicina
Rights© 2012 Fernández-Barral et al.
Esta obra está bajo una Licencia Creative Commons Atribución 4.0 Internacional.
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
Google Scholar:Fernández-Barral, Asunción - Orgaz, José Luis - Gómez, Valentí - Del Peso, Luis - Calzada, María José - Jiménez, Benilde
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