p53-independent NOXA induction overcomes apoptotic resistance of malignant melanomas

Jian Zhong Qin, Lawrence Stennett, Patricia Bacon, Barbara Bodner, Mary J.C. Hendrix, Richard E.B. Seftor, Elisabeth A. Seftor, Naira V. Margaryan, Pamela M. Pollock, Amy Curtis, Jeffrey M. Trent, Frank Bennett, Lucio Miele, Brian J. Nickoloff*

*Corresponding author for this work

Research output: Contribution to journalArticle

111 Scopus citations

Abstract

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 γ-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.

Original languageEnglish (US)
Pages (from-to)895-902
Number of pages8
JournalMolecular cancer therapeutics
Volume3
Issue number8
StatePublished - Aug 2004

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Qin, J. Z., Stennett, L., Bacon, P., Bodner, B., Hendrix, M. J. C., Seftor, R. E. B., Seftor, E. A., Margaryan, N. V., Pollock, P. M., Curtis, A., Trent, J. M., Bennett, F., Miele, L., & Nickoloff, B. J. (2004). p53-independent NOXA induction overcomes apoptotic resistance of malignant melanomas. Molecular cancer therapeutics, 3(8), 895-902.