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PMID: 18924608 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Notch1 is an effector of Akt and hypoxia in melanoma development.

The Journal of clinical investigation ·Vol. 118 ·No. 11 ·2008-11-00 ·Pages 3660-70

Bedogni B, Warneke JA, Nickoloff BJ, Giaccia AJ, Powell MB

Abstract

Melanomas are highly aggressive neoplasms resistant to most conventional therapies. These tumors result from the interaction of altered intracellular tumor suppressors and oncogenes with the microenvironment in which these changes occur. We previously demonstrated that physiologic skin hypoxia contributes to melanomagenesis in conjunction with Akt activation. Here we show that Notch1 signaling is elevated in human melanoma samples and cell lines and is required for Akt and hypoxia to transform melanocytes in vitro. Notch1 facilitated melanoma development in a xenograft model by maintaining cell proliferation and by protecting cells from stress-induced cell death. Hyperactivated PI3K/Akt signaling led to upregulation of Notch1 through NF-kappaB activity, while the low oxygen content normally found in skin increased mRNA and protein levels of Notch1 via stabilization of HIF-1alpha. Taken together, these findings demonstrate that Notch1 is a key effector of both Akt and hypoxia in melanoma development and identify the Notch signaling pathway as a potential therapeutic target in melanoma treatment.

MeSH Terms
Animals Cell Line, Tumor Genes, Reporter Humans Hypoxia/metabolism Hypoxia-Inducible Factor 1, alpha Subunit/genetics,metabolism Luciferases/metabolism Male Melanocytes/metabolism Melanoma/genetics,pathology Mice Mice, SCID NF-kappa B/metabolism Proto-Oncogene Proteins c-akt/genetics,metabolism RNA, Messenger/metabolism Receptor, Notch1/genetics,metabolism Signal Transduction Up-Regulation Xenograft Model Antitumor Assays
Chemicals
Hypoxia-Inducible Factor 1, alpha Subunit NF-kappa B RNA, Messenger Receptor, Notch1 Luciferases Proto-Oncogene Proteins c-akt
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Bedogni Barbara
Division of Radiation and Cancer Biology, Stanford University, Stanford, California, USA.
Warneke James A
Nickoloff Brian J
Giaccia Amato J
Powell Marianne Broome
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI36157
Published
2008-11-00
Epub
2008-00-16
Pages
3660-70
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC2567838
Subset
IM
Grants
NCI NIH HHS · P01 CA027502 · United States
NCI NIH HHS · R01 CA120526 · United States
NCI NIH HHS · P01CA27502 · United States
NCI NIH HHS · R01CA120526 · United States
External Links
PubMed source DOI: 10.1172/JCI36157 PMC Full Text View journal details
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