Notch and NOXA-related pathways in melanoma cells
Nickoloff, Brian J. , Hendrix, Mary J.C. , Pollock, Pamela M., Trent, Jeffrey M. , Miele, Lucio , & Qin, Jian-Zhong (2005) Notch and NOXA-related pathways in melanoma cells. Journal of Investigative Dermatology Symposium Proceedings, 10(2), pp. 95-104.
Notch receptor-mediated intracellular events represent an ancient cell signaling system, and alterations in Notch expression are associated with various malignancies in which Notch may function as an oncogene or less commonly as a tumor suppressor. Notch signaling regulates cell fate decisions in the epidermis, including influencing stem cell dynamics and growth/differentiation control of cells in skin. Because of increasing evidence that the Notch signaling network is deregulated in human malignancies, Notch receptors have become attractive targets for selective killing of malignant cells. Compared with proliferating normal human melanocytes, melanoma cell lines are characterized by markedly enhanced levels of activated Notch-1 receptor. By using a small molecule gamma-secretase inhibitor (GSI) consisting of a tripeptide aldehyde, N-benzyloxycarbonyl-Leu-Leu-Nle-CHO, which can block processing and activation of all four different Notch receptors, we identified a specific apoptotic vulnerability in melanoma cells. GSI triggers apoptosis in melanoma cells, but only G2/M growth arrest in melanocytes without subsequent cell death. Moreover, GSI treatment induced a pro-apoptotic BH3-only protein, NOXA, in melanoma cells but not in normal melanocytes. The use of GSI to induce NOXA induction overcomes the apoptotic resistance of melanoma cells, which commonly express numerous cell survival proteins such as Mcl-1, Bcl-2, and survivin. Taken together, these results highlight the concept of synthetic lethality in which exposure to GSI, in combination with melanoma cells overexpressing activated Notch receptors, has lethal consequences, producing selective killing of melanoma cells, while sparing normal melanocytes. By identifying signaling pathways that contribute to the transformation of melanoma cells (e.g. Notch signaling), and anti-cancer agents that achieve tumor selectivity (e.g., GSI-induced NOXA), this experimental approach provides a useful framework for future therapeutic strategies in cutaneous oncology.
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|Keywords:||Amyloid Precursor Protein Secretases, Aspartic Acid Endopeptidases, Endopeptidases/physiology, Genes, Tumor Suppressor, Humans, Melanoma/drug therapy/ etiology, Protease Inhibitors/pharmacology, Proto-Oncogene Proteins c-bcl-2/ physiology, Proto-Oncogenes, Receptors, Notch/ physiology, Signal Transduction/ physiology, ras Proteins/physiology|
|Subjects:||Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200) > Cancer Cell Biology (111201)|
|Divisions:||Past > Schools > Cell & Molecular Biosciences|
Past > QUT Faculties & Divisions > Faculty of Science and Technology
Current > Institutes > Institute of Health and Biomedical Innovation
|Copyright Owner:||Copyright 2005 The Society for Investigative Dermatology, Inc|
|Deposited On:||15 Sep 2011 15:42|
|Last Modified:||15 Sep 2011 15:42|
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