The hypoxic microenvironment of the skin contributes to Akt-mediated melanocyte transformation.
Cancer Cell
; 8(6): 443-54, 2005 Dec.
Article
in En
| MEDLINE
| ID: mdl-16338658
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.
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Database:
MEDLINE
Main subject:
Skin
/
Cell Hypoxia
/
Cell Transformation, Neoplastic
/
Proto-Oncogene Proteins c-akt
/
Melanocytes
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Cancer Cell
Journal subject:
NEOPLASIAS
Year:
2005
Type:
Article
Affiliation country:
United States