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PMID: 18451171 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Akt3 and mutant V600E B-Raf cooperate to promote early melanoma development.

Cancer research ·Vol. 68 ·No. 9 ·2008-05-01 ·Pages 3429-39

Cheung M, Sharma A, Madhunapantula SV, Robertson GP

Abstract

B-Raf is the most mutated gene in melanoma; however, the mechanism through which it promotes early melanomas remains uncertain. Most nevi contain activated (V600E)B-Raf but few develop into melanoma, and expression in melanocytes is inhibitory with low protein levels present in surviving cells, suggesting unknown cooperative oncogenic events are necessary for melanoma development. Because many melanomas have (V600E)B-Raf and active Akt3, it is possible that these proteins cooperatively facilitate melanocyte transformation. In this study, Akt3 is shown to phosphorylate (V600E)B-Raf to lower its activity as well as that of the downstream mitogen-activated protein kinase (MAPK) pathway to levels promoting early melanoma development. Expression of active Akt3 in early melanoma cells containing (V600E)B-Raf reduced MAPK signaling and promoted anchorage-independent growth. Furthermore, expression of both (V600E)B-Raf and active Akt3 in melanocytes promoted a transformed phenotype. Mechanistically, aberrant Akt3 activity in early melanomas serves to phosphorylate Ser(364) and Ser(428) on (V600E)B-Raf to reduce activity of (V600E)B-Raf to levels that promote rather than inhibit proliferation, which aids melanocytic transformation. Inhibition of (V600E)B-Raf or Akt3 in advanced melanoma cells in which both pathways were active reduced anchorage-independent growth and tumor development in a cooperatively acting manner. Inhibition of Akt3 alone in these cells led to increased MAPK signaling. In summary, these results suggest that activating B-Raf mutations initially promote nevi development, but the resulting high, intense activation of the MAPK pathway inhibits further tumor progression requiring Akt3 activation to bypass this barrier and aid melanoma development.

MeSH Terms
Animals Cell Adhesion/drug effects,genetics Cell Proliferation/drug effects Cell Transformation, Neoplastic/genetics Cells, Cultured Chromones/pharmacology Disease Progression Glutamic Acid/genetics Humans MAP Kinase Signaling System/drug effects Melanocytes/drug effects,enzymology,metabolism Melanoma/genetics Mice Morpholines/pharmacology Mutant Proteins/physiology Phosphoinositide-3 Kinase Inhibitors Proto-Oncogene Proteins B-raf/genetics,physiology Proto-Oncogene Proteins c-akt/physiology Signal Transduction/drug effects Valine/genetics
Chemicals
Chromones Morpholines Mutant Proteins Phosphoinositide-3 Kinase Inhibitors 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one Glutamic Acid AKT3 protein, human BRAF protein, human Proto-Oncogene Proteins B-raf Proto-Oncogene Proteins c-akt Valine
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Cheung Mitchell
Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
Sharma Arati
Madhunapantula SubbaRao V
Robertson Gavin P
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Article Info
Journal
Cancer research
Abbr.
Cancer Res
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-07-5867
Published
2008-05-01
Pages
3429-39
Language
English
Region
United States
NLM ID
2984705R
PMCID
PMC2603082
Subset
IM
Grants
NCI NIH HHS · R01 CA127892 · United States
NCI NIH HHS · R01 CA127892-01A1 · United States
NCI NIH HHS · CA-127892-01A1 · United States
External Links
PubMed source DOI: 10.1158/0008-5472.CAN-07-5867 PMC Full Text View journal details
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