[PDF][PDF] The hypoxic microenvironment of the skin contributes to Akt-mediated melanocyte transformation

B Bedogni, SM Welford, DS Cassarino, BJ Nickoloff… - Cancer cell, 2005 - cell.com
B Bedogni, SM Welford, DS Cassarino, BJ Nickoloff, AJ Giaccia, MB Powell
Cancer cell, 2005cell.com
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 HIF1α mediated. Inhibition of HIF1α decreases Akt transformation capacity in
hypoxia and tumor growth in vivo, while overexpression of HIF1α allows anchorage-
independent growth in normoxia and development of more aggressive tumors. Finally, we …
Summary
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 HIF1α mediated. Inhibition of HIF1α decreases Akt transformation capacity in hypoxia and tumor growth in vivo, while overexpression of HIF1α 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 HIF1α activity. Taken together, these findings demonstrate that Akt hyperactivation and HIF1α induction by normally occurring hypoxia in the skin significantly contribute to melanoma development.
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