Hypoxia promotes uveal melanoma invasion through enhanced Notch and MAPK activation

The transcriptional response promoted by hypoxia-inducible factors has been associated with metastatic spread of uveal melanoma. We found expression of hypoxia-inducible factor 1α (HIF-1α) protein in well-vascularized tumor regions as well as in four cell lines grown in normoxia, thus this pathway m...

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Bibliographic Details
Published in:PloS one 2014-08, Vol.9 (8), p.e105372-e105372
Main Authors: Asnaghi, Laura, Lin, Michael H, Lim, Kah Suan, Lim, Kah Jing, Tripathy, Arushi, Wendeborn, Murilo, Merbs, Shannath L, Handa, James T, Sodhi, Akrit, Bar, Eli E, Eberhart, Charles G
Format: Article
Language:English
Subjects:
AKT protein
Cancer therapies
Cell adhesion & migration
Cell growth
Cell Line, Tumor
Digoxin
Digoxin - pharmacology
Enzyme Inhibitors - pharmacology
Extracellular matrix
Extracellular signal-regulated kinase
Genes
Growth factors
Humans
Hypoxia
Hypoxia - genetics
Hypoxia - metabolism
Hypoxia - pathology
Hypoxia-Inducible Factor 1, alpha Subunit - genetics
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Hypoxia-inducible factors
Inhibition
Kinases
Liquid oxygen
MAP kinase
MAP Kinase Signaling System - drug effects
MAP Kinase Signaling System - physiology
Medical prognosis
Medicine
Medicine and Health Sciences
Melanoma
Melanoma - genetics
Melanoma - metabolism
Melanoma - pathology
Metabolism
Metastases
Metastasis
Mutation
Neoplasm Invasiveness - pathology
Notch protein
Notch1 protein
Oxygen
Pathology
Pharmacology
Phosphorylation
Proteins
Proto-Oncogene Proteins c-akt - metabolism
Rapamycin
Receptors, Notch - genetics
Receptors, Notch - metabolism
Rodents
Signal transduction
Signal Transduction - drug effects
Signal Transduction - physiology
Signaling
Skin cancer
Transcription activation
Tumors
Uveal Neoplasms - genetics
Uveal Neoplasms - metabolism
Uveal Neoplasms - pathology
Vascular endothelial growth factor
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Summary:The transcriptional response promoted by hypoxia-inducible factors has been associated with metastatic spread of uveal melanoma. We found expression of hypoxia-inducible factor 1α (HIF-1α) protein in well-vascularized tumor regions as well as in four cell lines grown in normoxia, thus this pathway may be important even in well-oxygenated uveal melanoma cells. HIF-1α protein accumulation in normoxia was inhibited by rapamycin. As expected, hypoxia (1% pO2) further induced HIF-1α protein levels along with its target genes VEGF and LOX. Growth in hypoxia significantly increased cellular invasion of all 5 uveal melanoma lines tested, as did the introduction of an oxygen-insensitive HIF-1α mutant into Mel285 cells with low HIF-1α baseline levels. In contrast, HIF-1α knockdown using shRNA significantly decreased growth in hypoxia, and reduced by more than 50% tumor invasion in four lines with high HIF-1α baseline levels. Pharmacologic blockade of HIF-1α protein expression using digoxin dramatically suppressed cellular invasion both in normoxia and in hypoxia. We found that Notch pathway components, including Jag1-2 ligands, Hes1-Hey1 targets and the intracellular domain of Notch1, were increased in hypoxia, as well as the phosphorylation levels of Erk1-2 and Akt. Pharmacologic and genetic inhibition of Notch largely blocked the hypoxic induction of invasion as did the pharmacologic suppression of Erk1-2 activity. In addition, the increase in Erk1-2 and Akt phosphorylation by hypoxia was partially reduced by inhibiting Notch signaling. Our findings support the functional importance of HIF-1α signaling in promoting the invasive capacity of uveal melanoma cells in both hypoxia and normoxia, and suggest that pharmacologically targeting HIF-1α pathway directly or through blockade of Notch or Erk1-2 pathways can slow tumor spread.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0105372