Abstract
Constitutive activation of Akt characterizes a high percentage of human melanomas and represents a poor prognostic factor of the disease. We show that Akt transforms melanocytes only in a hypoxic environment, which is found in normal skin. The synergy between Akt and hypoxia is HIF1alpha mediated. Inhibition of HIF1alpha decreases Akt transformation capacity in hypoxia and tumor growth in vivo, while overexpression of HIF1alpha allows anchorage-independent growth in normoxia and development of more aggressive tumors. Finally, we show that mTOR activity is necessary to maintain the transformed phenotype by sustaining HIF1alpha activity. Taken together, these findings demonstrate that Akt hyperactivation and HIF1alpha induction by normally occurring hypoxia in the skin significantly contribute to melanoma development.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Cell Hypoxia / physiology*
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Cell Line
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Cell Proliferation / drug effects
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Cell Transformation, Neoplastic / metabolism*
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Male
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Melanocytes / metabolism
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Melanocytes / physiology*
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Mice
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Mice, Knockout
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Mice, SCID
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Oxygen / metabolism
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Phenotype
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Protein Kinases / drug effects
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Protein Kinases / metabolism
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism*
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Sirolimus / pharmacology
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Skin / metabolism*
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TOR Serine-Threonine Kinases
Substances
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Protein Kinases
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MTOR protein, human
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mTOR protein, mouse
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Oxygen
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Sirolimus