title: HIF-1α stabilization by mitochondrial ROS promotes Met-dependent invasive growth and vasculogenic mimicry in melanoma cells.
abstract: The "angiogenic switch" during tumor progression is increasingly recognized as a milestone event in tumorigenesis, although the surprising prometastatic effect of antiangiogenic therapies has recently shaken the scientific community. Tumor hypoxia has been singled out as a possible responsible factor in this prometastatic effect, although the molecular pathways are completely unknown. We report herein that human melanoma cells respond to hypoxia through a deregulation of the mitochondrial release of reactive oxygen species (ROS) by the electron transfer chain complex III. These ROS are mandatory to stabilize hypoxia-inducible factor-1α (HIF-1α), the master transcriptional regulator of the hypoxic response. We found that melanoma cells sense hypoxia-enhancing expression/activation of the Met proto-oncogene, which drives a motogenic escape program. Silencing analyses revealed a definite hierarchy of this process, in which mitochondrial ROS drive HIF-1α stabilization, which in turn activates the Met proto-oncogene. This pathway elicits a clear metastatic program of melanoma cells, enhancing spreading on extracellular matrix, motility, and invasion of 3D matrices, as well as growth of metastatic colonies and the ability to form capillary-like structures by vasculogenic mimicry. Both pharmacological and genetic interference with mitochondrial ROS delivery or Met expression block the hypoxia-driven metastatic program. Hence, we propose that hypoxia-driven ROS act as a primary driving force to elicit an invasive program exploited by aggressive melanoma cells to escape from a hypoxic hostile environment.
authors.affiliation: Department of Biochemical Sciences, University of Florence, 50134 Firenze, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Comito
authors.forename: Maura
authors.initials: M
authors.lastname: Calvani
authors.forename: Elisa
authors.initials: E
authors.lastname: Giannoni
authors.forename: Francesca
authors.initials: F
authors.lastname: Bianchini
authors.forename: Lido
authors.initials: L
authors.lastname: Calorini
authors.forename: Eugenio
authors.initials: E
authors.lastname: Torre
authors.forename: Cristina
authors.initials: C
authors.lastname: Migliore
authors.forename: Silvia
authors.initials: S
authors.lastname: Giordano
authors.forename: Paola
authors.initials: P
authors.lastname: Chiarugi
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D018450:Disease Progression; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000276:immunology / Q000378:metabolism*; D008175:Lung Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000503:physiopathology / Q000556:secondary; D008545:Melanoma / Q000098:blood supply / Q000378:metabolism* / Q000503:physiopathology / Q000556:secondary; D051379:Mice; D016513:Mice, SCID; D008928:Mitochondria / Q000378:metabolism*; D009374:Neoplasms, Experimental; D009389:Neovascularization, Pathologic / Q000235:genetics; D055550:Protein Stability; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D047368:Tumor Burden
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D019859:Proto-Oncogene Proteins c-met