| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
1 Department of Pathology, Loyola University of Chicago Medical Center, Chicago, Illinois; 2 Children's Memorial Institute for Education and Research, Northwestern University Feinberg School of Medicine, Chicago, Illinois; 3 Translational Genomics Research Institute, Phoenix, Arizona; 4 ISIS Pharmaceuticals, Carlsbad, California; and 5 Department of Biopharmaceutical Sciences, University of Illinois, Chicago, Illinois
Request for reprints: Brian J. Nickoloff, Skin Cancer Research Program, Cardinal Bernardin Cancer Center, Building 112, Room 301, 2160 South First Avenue, Maywood, IL 60153. Phone: 708-327-3241; Fax: 708-327-3239. E-mail: bnickol{at}lumc.edu
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 
-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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 4/30/04; revised 6/16/04; accepted 6/23/04.
This article has been cited by other articles:
|
|
 |
|
  Y. Nefedova, D. M. Sullivan, S. C. Bolick, W. S. Dalton, and D. I. Gabrilovich Inhibition of Notch signaling induces apoptosis of myeloma cells and enhances sensitivity to chemotherapy Blood, February 15, 2008; 111(4): 2220 - 2229. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. F. Gajewski, E. A. Grimm, B. J. Nickoloff, and A. T. Weeraratna New Potential Therapeutic Targets in Melanoma ASCO Educational Book, January 1, 2008; 2008(1): 404 - 407. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Konishi, K. S. Kawaguchi, H. Vo, N. Haruki, A. Gonzalez, D. P. Carbone, and T. P. Dang {gamma}-Secretase Inhibitor Prevents Notch3 Activation and Reduces Proliferation in Human Lung Cancers Cancer Res., September 1, 2007; 67(17): 8051 - 8057. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Han, L. A. Goldstein, W. Hou, and H. Rabinowich Functional Linkage between NOXA and Bim in Mitochondrial Apoptotic Events J. Biol. Chem., June 1, 2007; 282(22): 16223 - 16231. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Bolos, J. Grego-Bessa, and J. L. de la Pompa Notch Signaling in Development and Cancer Endocr. Rev., May 1, 2007; 28(3): 339 - 363. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-Z. Qin, H. Xin, L. A. Sitailo, M. F. Denning, and B. J. Nickoloff Enhanced Killing of Melanoma Cells by Simultaneously Targeting Mcl-1 and NOXA Cancer Res., October 1, 2006; 66(19): 9636 - 9645. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Akhtar, Y. Geng, B. J. Klocke, C. B. Latham, A. Villunger, E. M. Michalak, A. Strasser, S. L. Carroll, and K. A. Roth BH3-only proapoptotic Bcl-2 family members Noxa and Puma mediate neural precursor cell death. J. Neurosci., July 5, 2006; 26(27): 7257 - 7264. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Miele Notch Signaling Clin. Cancer Res., February 15, 2006; 12(4): 1074 - 1079. [Full Text] [PDF]
|
|
|
|
|
|
P. Perez-Galan, G. Roue, N. Villamor, E. Montserrat, E. Campo, and D. Colomer The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status Blood, January 1, 2006; 107(1): 257 - 264. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-Z. Qin, J. Ziffra, L. Stennett, B. Bodner, B. K. Bonish, V. Chaturvedi, F. Bennett, P. M. Pollock, J. M. Trent, M. J.C. Hendrix, et al. Proteasome Inhibitors Trigger NOXA-Mediated Apoptosis in Melanoma and Myeloma Cells Cancer Res., July 15, 2005; 65(14): 6282 - 6293. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Fernandez, M. Verhaegen, T. P. Miller, J. L. Rush, P. Steiner, A. W. Opipari Jr., S. W. Lowe, and M. S. Soengas Differential Regulation of Noxa in Normal Melanocytes and Melanoma Cells by Proteasome Inhibition: Therapeutic Implications Cancer Res., July 15, 2005; 65(14): 6294 - 6304. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. C. Cuevas, A. L. Slocum, P. Jun, J. F. Costello, A. W. Bollen, G. J. Riggins, M. W. McDermott, and A. Lal Meningioma Transcript Profiles Reveal Deregulated Notch Signaling Pathway Cancer Res., June 15, 2005; 65(12): 5070 - 5075. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
