The hypoxic microenvironment of the skin contributes to Akt-mediated melanocyte transformation.
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.
Bedogni
Barbara
B
Division of Radiation and Cancer Biology, Stanford University, Stanford, California 94305, USA.
Welford
Scott M
SM
Cassarino
David S
DS
Nickoloff
Brian J
BJ
Giaccia
Amato J
AJ
Powell
Marianne Broome
MB
D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008544:Melanocytes / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D010100:Oxygen / Q000378:metabolism; D010641:Phenotype; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D012867:Skin / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D010100:Oxygen; D020123:Sirolimus