Original ContributionHIF-1α stabilization by mitochondrial ROS promotes Met-dependent invasive growth and vasculogenic mimicry in melanoma cells
Section snippets
Materials
Unless specified all reagents were obtained from Sigma. Hs29-4T cells were from the ATCC, all antibodies were from Santa Cruz Biotechnology, except for the anti-HIF-1α, which was from BD Biosciences. 2′,7′-Dichlorofluorescein diacetate (DCF-DA) was from Molecular Probes and the ATP-competitive inhibitor of Met kinase PHA-665752 (PHA) was from Tocris. Polyvinylidene difluoride was from Millipore and Matrigel was from BD Biosciences. siRNA oligonucleotides targeting HIF-1α (target sequence
Hypoxia induces a more aggressive phenotype in Hs29-4T melanoma cells
A preliminary screening of growth factor receptors (GF-Rs) regulated by hypoxia on Hs29-4T melanoma cells, including HGF-R/Met, VEGF-R1, VEGF-R2, EphA2, EphA3, EphB2, platelet derived growth factor β receptor (PDGF-R), and fibroblast growth factor-2 receptor, indicated that 1% O2 mainly leads to increased expression of Met, showing only a marginal effect on VEGF-R2 and being ineffective at the regulation of the other GF-Rs (Supplementary Fig. 1). Hs29-4T melanoma cells were exposed for 24 h to
Discussion
The results presented in this report lead to these major conclusions: (1) in Hs29-4T human melanoma cells hypoxia leads to a redox-dependent stabilization of HIF-1α, mainly mediated by mitochondrial ROS, and (2) HIF-1α accumulation, in turn, leads to enhanced expression and activation of the proto-oncogene Met and to activation of: (i) the motogenic program, (ii) invasiveness and ability to disseminate metastatic colonies of melanoma cells, and (iii) the skill to mimic the vasculature, forming
Acknowledgments
This work was supported by the Associazione Italiana Ricerca sul Cancro, Istituto Toscano Tumori, Region Toscana, and Fondazione Cassa di Risparmio di Lucca.
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