p53-independent NOXA induction overcomes apoptotic resistance of malignant melanomas

Qin, Jian-Zhong, Stennett, Lawrence, Bacon, Patricia, Bodner, Barbara, Hendrix, Mary J.C., Seftor, Richard E.B., Seftor, Elisabeth A., Margaryan, Naira V., Pollock, Pamela M., Curtis, Amy, Trent, Jeffrey M., Bennett, Frank, Miele, Lucio, & Nickoloff, Brian J. (2004) p53-independent NOXA induction overcomes apoptotic resistance of malignant melanomas. Molecular Cancer Therapeutics, 3(8), pp. 895-902.

View at publisher (open access)


Once melanoma metastasizes, no effective treatment modalities prolong survival in most patients. This notorious refractoriness to therapy challenges investigators to identify agents that overcome melanoma resistance to apoptosis. Whereas many survival pathways contribute to the death-defying phenotype in melanoma, a defect in apoptotic machinery previously highlighted inactivation of Apaf-1, an apoptosome component engaged after mitochondrial damage. During studies involving Notch signaling in melanoma, we observed a gamma-secretase tripeptide inhibitor (GSI; z-Leu-Leu-Nle-CHO), selected from a group of compounds originally used in Alzheimer's disease, induced apoptosis in nine of nine melanoma lines. GSI only induced G2-M growth arrest (but not killing) in five of five normal melanocyte cultures tested. Effective killing of melanoma cells by GSI involved new protein synthesis and a mitochondrial-based pathway mediated by up-regulation of BH3-only members (Bim and NOXA). p53 activation was not necessary for up-regulation of NOXA in melanoma cells. Blocking GSI-induced NOXA using an antisense (but not control) oligonucleotide significantly reduced the apoptotic response. GSI also killed melanoma cell lines with low Apaf-1 levels. We conclude that GSI is highly effective in killing melanoma cells while sparing normal melanocytes. Direct enhancement of BH3-only proteins executes an apoptotic program overcoming resistance of this lethal tumor. Identification of a p53-independent apoptotic pathway in melanoma cells, including cells with low Apaf-1, bypasses an impediment to current cytotoxic therapy and provides new targets for future therapeutic trials involving chemoresistant tumors.

Impact and interest:

101 citations in Scopus
Search Google Scholar™
99 citations in Web of Science®

Citation counts are sourced monthly from Scopus and Web of Science® citation databases.

These databases contain citations from different subsets of available publications and different time periods and thus the citation count from each is usually different. Some works are not in either database and no count is displayed. Scopus includes citations from articles published in 1996 onwards, and Web of Science® generally from 1980 onwards.

Citations counts from the Google Scholar™ indexing service can be viewed at the linked Google Scholar™ search.

ID Code: 45826
Item Type: Journal Article
Refereed: Yes
Additional Information: Articles free to read on journal website after 12 months
Keywords: Annexin A5/pharmacology, Apoptosis, Apoptotic Protease-Activating Factor 1, Cell Division, Cell Line, Tumor, Cell Survival, Cycloheximide/pharmacology, Dose-Response Relationship, Drug, G2 Phase, Humans, Immunoblotting, Melanocytes/metabolism, Melanoma/ pathology, Membrane Proteins/metabolism, Mitochondria/metabolism, Models, Biological, Neoplasm Metastasis, Oligonucleotides, Antisense/pharmacology, Phenotype, Proteins/metabolism, Proto-Oncogene Proteins c-bcl-2/ metabolism, RNA, Small Interfering/metabolism, Receptors, Notch, Signal Transduction, Subcellular Fractions, Time Factors, Tumor Suppressor Protein p53/metabolism/ physiology, Up-Regulation
ISSN: 1535-7163
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 2004 American Association for Cancer Research
Deposited On: 08 Sep 2011 22:04
Last Modified: 22 Apr 2015 22:56

Export: EndNote | Dublin Core | BibTeX

Repository Staff Only: item control page